6,7-unsaturated-7-carbamoyl substituted morphinan derivative

ABSTRACT

A novel compound which is useful as an agent for treating and/or preventing emesis, vomiting and/or constipation. 
     A compound represented by the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl etc., R 3  is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy etc., R 4  is hydrogen or lower alkyl, R 5  is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl,
 
or a pharmaceutically acceptably salt, or a solvate thereof is provided.

TECHNICAL FIELD

The present invention relates to a6,7-unsaturated-7-carbamoyl-substutaed morphinan derivatives, which areuseful as an agent for treating and/or preventing nausea, emesis,vomiting and/or constipation, particularly as an agent for alleviatingand/or preventing a side effect (emesis, vomiting and/or constipationetc.) induced by a compound having the opioid receptor (e.g. opioid μreceptor) agonistic activity.

BACKGROUND ART

An opioid receptor agonist such as morphine and the like which is usedas an analgesic is very effective in a patient having cancer pain, butas a side effect, induces severe nausea, emesis, vomiting, constipation,anuresis, and itching. Various antiemetics and anti-constipation agentsare clinically used, but it can not be said that any of them exhibitsthe sufficient effect, and an excellent side effect alleviating agent isalso demanded for improving QOL of a patient.

Patent Literatures 1 and 2, and Non-patent Literature 1 describe to theeffect that a morphinan derivative is effective in treating orpreventing emesis and vomiting induced by an opioid μ agonist, andNon-Patent Literature 2 describes that a6,7-saturated-7-carbamoyl-substituted-morphinan derivatives have theopioid δ receptor antagonism. However, none of them describes orsuggests the present compound.

-   [Patent Literature 1] International Patent Application Publication    WO 2004-007503-   [Patent Literature 2] International Patent Application Publication    WO 95/13071-   [Non-Patent Literature 1] Journal of Medicinal Chemistry 41,    4177-4180 (1998)-   [Non-Patent Literature 2] Chemical and Pharmaceutical Bulletin,    52 (66) 747-750 (2004)

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

We found 6,7-unsaturated-7-carbamoyl-substituted morphinan derivativesuseful as a composition for treating and/or preventing emesis, vomitingand/or constipation.

Means to Solve the Problems

The present invention provides:

(1) a compound represented by the formula (I):

wherein R¹ and R² are each independently hydrogen, optionallysubstituted lower alkyl, optionally substituted lower alkenyl,optionally substituted lower alkynyl, optionally substituted loweralkylsulfonyl, optionally substituted acyl, optionally substitutedcycloalkyl, optionally substituted cycloalkenyl, optionally substitutedaryl, an optionally substituted heterocyclic group, or optionallysubstituted arylsulfonyl, or R¹ and R² are taken together with thenitrogen atom to which they are attached to form optionally substitutedheterocycle;R³ is hydrogen, hydroxy, optionally substituted lower alkyl, loweroptionally substituted lower alkenyl, optionally substituted loweralkynyl optionally substituted lower alkoxy, mercapto, optionallysubstituted lower alkylthio, optionally substituted amino, optionallysubstituted carbamoyl, optionally substituted acyl, optionallysubstituted acyloxy, optionally substituted aryl, or an optionallysubstituted heterocyclic group,a group represented by the formula:

wherein ring A or ring B are each independently optionally substitutednitrogen-containing heterocycle optionally containing additionalnitrogen atom, an oxygen atom, and/or a sulfur atom in the ring;broken line indicates the presence or the absence of a bond;when a broken line indicates the presence of a bond, p is 0;when a broken line indicates the absence of a bond, p is 1;R^(a) is hydrogen, optionally substituted lower alkyl, optionallysubstituted lower alkenyl, or optionally substituted lower alkynyl;and R^(b) is hydrogen or oxo;R⁴ is hydrogen or lower alkyl;R⁵ is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl,or a pharmaceutically acceptable salt, or a solvate thereof,(1′) a compound represented by the formula (I):

wherein R¹ and R² are each independently hydrogen, optionallysubstituted lower alkyl, optionally substituted lower alkenyl,optionally substituted cycloalkyl, optionally substituted aryl, or anoptionally substituted heterocyclic group, or R¹ and R² are takentogether with the nitrogen atom to which they are attached to formoptionally substituted heterocycle;R³ is hydrogen, hydroxy, optionally substituted lower alkyl, optionallysubstituted lower alkenyl, optionally substituted lower alkynyl,optionally substituted lower alkoxy, mercapto, optionally substitutedlower alkylthio, optionally substituted aryl, or an optionallysubstituted heterocyclic group;R⁴ is hydrogen or lower alkyl;and R⁵ is hydrogen, lower alkyl, cycloalkyl lower alkyl or loweralkenyl;or a pharmaceutically acceptable salt, or a solvate thereof,(2) the compound according to (1) or (1′), wherein R³ is hydroxy,or a pharmaceutically acceptable salt, or a solvate thereof,(3) the compound according to (1) or (1′), wherein R³ is optionallysubstituted amino,or a pharmaceutically acceptable salt, or a solvate thereof,(4) the compound according to (1) or (1′), wherein R³ is aminosubstituted with optionally substituted arylsulfonyl,or a pharmaceutically acceptable salt, or a solvate thereof,(5) the compound according to any one of (1) to (4), and (1′), whereinR¹ is hydrogen or lower alkyl, R² is optionally substituted lower alkyl,optionally substituted phenyl, optionally substituted cycloalkyl, or anoptionally substituted heterocyclic group, and R⁵ is cyclopropylmethyl;or a pharmaceutically acceptable salt, or a solvate thereof,(6) the compound according to any one of (1) to (5), and (1′), whereinR¹ is hydrogen, R² is lower alkyl optionally substituted with aheterocyclic group or lower alkoxy optionally substituted with aryl,phenyl optionally substituted with lower alkyl or lower alkoxy,cycloalkyl substituted with lower alkylcarbonyl, or a heterocyclic groupsubstituted with lower alkoxy or aryl, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,or a pharmaceutically acceptable salt, or a solvate thereof,(7) a pharmaceutical composition containing the compound according toany one of (1) to (6), and (1′), or a pharmaceutically acceptable salt,or a solvate thereof,(8) a composition having opioid receptor antagonistic activitycontaining the compound according to (1) to (6), and (1′), or apharmaceutically acceptable salt, or a solvate thereof,(9) a composition for treating and/or preventing emesis, vomiting and/orconstipation containing the compound according to any one of (1) to (6),and (1′), or a pharmaceutically acceptable salt, or a solvate thereof,(10) a composition for alleviating and/or preventing a side effectinduced by a compound having the opioid receptor agonistic activity,containing the compound according to any one of (1) to (6), and (1′), ora pharmaceutically acceptable salt, or a solvate thereof,(11) a composition for treatment and/or prevention according to (10),wherein the side effect is emesis, vomiting and/or constipation,(12) an agent for treatment and/or prevention according to (10) or (11),wherein the compound having the opioid receptor agonistic activity ismorphine, oxycodone, or a pharmaceutically acceptable salt, or a solvatethereof,(13) use of the compound according to any one of (1) to (6), and (1′),or a pharmaceutically acceptable salt, or solvate thereof for producinga medicament for treating and/or preventing emesis, vomiting and/orconstipation,(14) use of the compound according to any one of (1) to (6), and (1′),or a pharmaceutically acceptable salt, or solvate thereof, for producinga medicament for alleviating and/or preventing a side effect induced bya compound having the opioid receptor agonistic activity,(15) a method for treating and/or preventing emesis, vomiting and/orconstipation, comprising administering the compound according to any oneof (1) to (6) and (1′), or a pharmaceutically acceptable salt, or asolvate thereof,(16) a method for alleviating and/or preventing a side effect induced bya compound having the opioid receptor agonistic activity, comprisingadministering the compound according to any one of (1) to (6) and (1′),its pharmaceutically acceptable salt, or a solvate thereof,(17) a composition for analgesic containinga compound having an opioid receptor agonistic activity,and an effective amount of compound according to any one of (1) to (6)and (1′), or a pharmaceutically acceptable salt, or a solvate thereof,for alleviating and/or preventing a side effect induced byadministration of the compound having an opioid receptor agonisticactivity,(18) a composition for analgesic containinga compound having an opioid receptor agonistic activity,and an effective amount of compound according to any one of (1) to (6)and (1′), or a pharmaceutically acceptable salt or a solvate thereof,for treating and/or preventing emesis, vomiting and/or constipationinduced by administration of the compound having an opioid receptoragonistic activity,(19) the analgesic according to (17) or (18), wherein the compoundhaving the opioid receptor agonistic activity, is morphine, oxycodone,its pharmaceutically acceptable salt, or a solvate thereof.

Effect of the Invention

The compound (I) of the present invention has the activity oftreating/or preventing emesis, vomiting and/or constipation,particularly emesis, vomiting and/or constipation induced by a compoundhaving the opioid receptor (e.g. opioid μ receptor) agonistic activity,and is useful as a compositon for alleviating a side effect of a patientto whom a compound having the opioid receptor agonistic activity isadministered or is in the middle of administration.

BEST MODE FOR CARRYING OUT THE INVENTION

As used herein, the “halogen” includes fluorine, chlorine, bromine andiodine. A halogen part of the “halogeno lower alkyl”, the “halogenolower alkoxy”, and the “halogeno lower alkylthio” is the same.

The “lower alkyl” includes a straight or branched alkyl of a carbonnumber of 1 to 10, preferably a carbon number of 1 to 6, furtherpreferably 1 to 3, and examples include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl,isooctyl, n-nonyl and n-decyl. Preferable are methyl, ethyl, isopropyl,n-butyl, sec-butyl, tert-butyl, and 1-ethylpropyl.

Examples of a substituent of the “optionally substituted lower alkyl”include halogen, hydroxy, lower alkoxy, halogeno lower alkoxy, hydroxylower alkoxy, lower alkylthio, lower alkylamino, acylamino, acyl,acyloxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, loweralkylcarbamoyl, cyanocarbamoyl, lower alkylsulfonylcarbamoyl,arylsulfonylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, loweralkylsulfonyl, cycloalkyl optionally substituted with one or moresubstituents selected from Substituent group α (wherein Substituentgroup α is halogen, hydroxy, lower alkyl, halogeno lower alkyl, hydroxylower alkyl, lower alkoxy lower alkyl, carboxy lower alkyl, loweralkoxycarbonyl lower alkyl, amino lower alkyl, lower alkylamino loweralkyl, acylamino lower alkyl, cyano lower alkyl, lower alkoxy, halogenolower alkoxy, hydroxy lower alkoxy, lower alkylthio, halogeno loweralkylthio, acyl, acyloxy, amino, lower alkylamino, acylamino, cyano,carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl,arylcarbamoyl, cyanocarbamoyl, lower alkylsulfonylcarbamoyl, sulfamoyl,lower alkylsulfamoyl, lower alkylsulfonyl, aryl optionally substitutedwith lower alkylenedioxy, and a heterocyclic group), cycloalkenyloptionally substituted with one or more substituents selected fromSubstituent group α, aryl optionally substituted with one or moresubstituents selected from Substituent group α, aryloxy optionallysubstituted with one or more substituents selected from Substituentgroup α, arylthio optionally substituted with one or more substituentsselected from Substituent group α, a heterocyclic group optionallysubstituted with one or more substituents selected from Substituentgroup α, and heterocyclic oxy optionally substituted with one or moresubstituents selected from Substituent group α.

A lower alkyl part of the “halogeno lower alkyl”, the “hydroxy loweralkyl”, the “amino lower alkyl”, the “acylamino lower alkyl”, the“acyloxy lower alkyl”, the “cycloalkyl lower alkyl”, the “lower alkoxy”,the “halogeno lower alkoxy”, the “hydroxy lower alkoxy”, the “loweralkoxy lower alkyl”, the “lower alkoxycarbonyl”, the “carboxy loweralkyl”, the “lower alkoxycarbonyl lower alkyl”, the “lower alkylthio”,the “halogeno lower alkylthio”, the “lower alkylamino”, the “loweralkylamino lower alkyl”, the “lower alkylcarbamoyl”, the “loweralkylsulfamoyl”, the “lower alkylsulfonyl”, the “aryl lower alkyl”, the“tri lower alkylsilyl”, the “lower alkyldiarylsilyl”, the “triaryl loweralkylsilyl”, the “lower alkoxy lower alkoxy lower alkyl”, the “loweralkylthio lower alkyl”, the “aryl lower alkoxy lower alkyl”, the “loweralkylsulfonyl”, the “lower alkylsulfonylcarbamoyl”, the “loweralkylcarbonyl”, the “cyano lower alkyl”, the “loweralkoxycarbonylamino”, the “lower alkylenedioxy”, and the “heterocycliclower alkyl” is the same as that of the aforementioned “lower alkyl”.

A substituent of the “optionally substituted lower alkoxy”, the“optionally substituted lower alkylthio”, and the “optionallysubstituted lower alkylsulfonyl” is the same as the aforementionedsubstituent of the “optionally substituted lower alkyl”.

The “lower alkenyl” includes a straight or branched alkenyl of a carbonnumber of 2 to 10, preferably a carbon number of 2 to 8, furtherpreferably a carbon number of 3 to 6 having one or more double bonds atan arbitrary position. Specifically, examples include vinyl, allyl,propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl,pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl,heptenyl, octenyl, nonenyl and decenyl. The lower alkenyl in R⁵ ispreferably allyl.

The substituent of the “optionally substituted lower alkenyl” is thesame as that of the “optionally substituted lower alkyl”.

The “lower alkynyl” includes straight or branched alkynyl of a carbonnumber of 2 to 10, preferably a carbon number of 2 to 8, furtherpreferably a carbon number of 3 to 6 having one or more triple bonds atan arbitrary position. Specifically, examples include ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.These may further have a double bond at an arbitrary position.

The substituent of the “optionally substituted lower alkynyl” is thesame as that of the “optionally substituted lower alkyl”.

Examples of the substituent of the “optionally substituted amino”include lower alkyl optionally substituted with one or more substituentsselected from Substituent group α, cycloalkyl optionally substitutedwith one or more substituents selected from Substituent group α, acyloptionally substituted with one or more substituents selected fromSubstituent group α, amino optionally substituted with one or moresubstituents selected from Substituent group α, aryl optionallysubstituted with one or more substituents selected from Substituentgroup α, sulfamoyl, lower alkylsulfamoyl optionally substituted with oneor more substituents selected from Substituent group α, arylsulfamoyloptionally substituted with one or more substituents selected fromSubstituent group α, lower alkylsulfonyl optionally substituted with oneor more substituents selected from Substituent group α, arylsulfonyloptionally substituted with one or more substituents selected fromSubstituent group α, arylamino optionally substituted with one or moresubstituents selected from Substituent group α, and a heterocyclic groupoptionally substituted with one or more substituents selected fromSubstituent group α.

The substituent of the “optionally substituted carbamoyl” is the same asthat of the “optionally substituted amino”.

The “cycloalkyl” is a carbocyclic group of a carbon number of 3 to 10,preferably a carbon number of 3 to 8, more preferably a carbon number of4 to 8 and, for example, includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Thesemay be further condensed with “aryl” described later or “heterocyclicgroup” described later at an arbitrary position.

As the “cycloalkyl” in R¹ and R², cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl are preferable.

A cycloalkyl part of the “cycloalkyl lower alkyl” and the“cycloalkylcarbonyl” is the same as the aforementioned “cycloalkyl”.

As the “cycloalkyl lower alkyl” in R⁵, cyclopropylmethyl is preferable.”

Examples of the substituent of the “optionally substituted cycloalkyl”include on or more substituents selected from the aforementionedSubstituent group α. The substituent can replace at an arbitraryposition, and may replace at a carbon atom having a bond of cycloalkyl.

The “cycloalkenyl” includes cycloalkenyl having one or more double bondsat an arbitrary position in a ring of the aforementioned cycloalkyl, andexamples include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptyl, cyclooctynyl and cyclohexadienyl.

As the “cycloalkenyl” in R¹ or R², cyclopropenyl, cyclobutenyl,cyclopentenyl, and cyclohexenyl are preferable.

A cycloalkenyl part of the “cycloalkenylcarbonyl” is the same as theaforementioned “cycloalkenyl”.

The substituent of the “optionally substituted cycloalkenyl” is the sameas that of the aforementioned “optionally substituted cycloalkyl”.

The “aryl” includes phenyl, naphthyl, anthryl and phenanthryl, andphenyl is particularly preferable.

An aryl part of the “aryloxy”, the “arylthio”, the “aryl lower alkyl”,the “lower alkyldiarylsilyl”, the “triaryl lower alkylsilyl”, the “aryllower alkyloxy lower alkyl”, the “arylsulfonyl”, the “arylsofamoyl”, the“arylamino”, the “arylcarbamoyl”, and the “arylsulfonylcarbamoyl” is thesame as the aforementioned “aryl”.

Examples of the substituent of the “optionally substituted aryl”, the“optionally substituted phenyl”, and the “optionally substitutedarylsulfonyl”, include the Substituent group α, phenyl substituted withone or more groups selected from Substituent group α, phenoxysubstituted with one or more groups selected from Substituent group α,and lower alkylenedioxy.

The “heterocyclic group” includes a heterocyclic group having one ormore heteroatoms arbitrarily selected from O, S and N in a ring, andspecifically includes a 5- to 6-membered heteroaryl such as pyrrolyl,imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl,isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl; a bicycliccondensed heterocyclic group such as indolyl, isoindolyl, indazolyl,indolidinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthridinyl, quinoxalinyl, purinyl,pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl,benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl,triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl,quinolyl, isoquinolyl, naphthyridinyl, dihydropyridyl,tetrahydroquinolyl, and tetrahydrobenzothienyl; a tricyclic condensedheterocyclic group such as carbazolyl, acridinyl, xanthenyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl; anon-aromatic heterocyclic group such as dioxanyl, thiiranyl, thioranyl,thietanyl, oxilanyl, oxetanyl, oxathioranyl, azetidinyl, thianyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino,thiomorpholinyl, thiomorpholino, dihydropyridyl, dihydrofuryl,tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, andtetrahydroisothiazolyl. Preferable is a 5- to 6-membered heteroaryl or anon-aromatic heterocyclic group.

As the “heterocyclic group” in R¹ and R², pyrazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl,thiadiazolyl, furyl, thienyl, indolyl, indazolyl, quinolyl, isoquinolyl,benzoxazolyl, benzothiazolyl, oxetanyl, tetrahydrofuryl, andtetrahydropyranyl are preferable. Pyridyl, pyridazinyl, pyrimidinyl, andpyrazinyl are more preferable. Pyridyl and pyrimidinyl are particularlypreferable.

As the heterocyclic group of the “optionally substituted lower alkyl” inR¹ and R², isoxazolyl, oxazolyl, and oxadiazolyl are preferable.Oxadiazolyl is particularly preferable.

A heterocyclic part of the “heterocyclic oxy” and the “heterocycliclower alkyl” is the same as the aforementioned “heterocyclic group”.

Examples of the substituent of the “optionally substituted heterocyclicgroup” include one or more groups selected from the group consisting ofthe Substituent group α and oxo. The substituent can replace at anarbitrary position, or may replace at a carbon atom or a nitrogen atomhaving a bond of the heterocyclic group.

The “acyl” includes straight or branched chain-like aliphatic acyl of acarbon number of 1 to 10, preferably a carbon number of 1 to 6, furtherpreferably a carbon number of 1 to 4, cyclic aliphatic acyl of a carbonnumber of 4 to 9, preferably a carbon number of 4 to 7, aroyl andheterocyclic carbonyl. Herein, the “chain-like aliphatic” includes theaforementioned “lower alkyl”, the aforementioned “lower alkenyl”, andthe aforementined “lower alkynyl”. The “cyclic aliphatic” includes theaforementioned “cycloalkyl” and the aforementioned “cycloalkenyl”. Aheterocyclic part of the heterocyclic carbonyl is the same as theaforementioned “heterocyclic group”. Examples of the acyl includeformyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl,hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl,cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl, benzoyl,pyridine carbonyl, piperidinecarbonyl, piperazinecarbonyl,morpholinocarbonyl, and the like.

An acyl part of the “acyloxy”, the “acylamino”, the “acylamino loweralkyl” and the “acyloxy lower alkyl” is the same as the aforementioned“acyl”.

The substituent of the “optionally substituted acyl” or the “optionallysubstituted” is the same as the substituent of the aforementioned“optionally substituted lower alkyl” when the “acyl” is chain-likealiphatic acyl, and includes one or more groups selected from theSubstituent group α when the “acyl” is cyclic aliphatic acyl, aroyl orheterocyclic carbonyl.

The “optionally substituted heterocycle” formed when R¹ and R² are takentogether with the nitrogen atom to which they are atttached, includes a5-membered or 6-membered heterocycle containing the nitrogen atom towhich R¹ and R² are attached and, further, optionally containing one ormore heteroatoms selected from N, S and O. For example, the case where

is a saturated heterocycle group such as

or an unsaturated heterocycle group such as

wherein R⁶, R⁷ and R⁸ are each independently hydrogen, halogen, hydroxy,lower alkyl, lower alkoxy, lower alkylthio, acyl, acyloxy, amino, loweralkylamino, acylamino, lower alkoxycarbonylamino, carboxy or loweralkoxycarbonyl,is included and the preferable is a saturated heterocycle group such asmorpholine ring, pyrrolidine ring, piperidine ring, piperazine ring, andthe like optionally substituted with hydrogen, halogen, hydroxy or loweralkyl.

The substituent of the “optionally substituted heterocycle, which isformed when R¹ and R² are taken together with the nitrogen atom to whichthey are attached” is the same as the substituent of the “optionallysubstituted heterocyclic group”.

includes, for example, the following:

wherein R^(a) is as defined above, and R is hydrogen or a group selectedfrom Substituent group α.

Herein, the “solvate” includes, for example, a solvate with an organicsolvent, a hydrate and the like. When a hydrate is formed, any number ofwater molecules may be coordinated.

The compound (I) includes a pharmaceutically acceptable salt. Examplesinclude salts with alkali metals (lithium, sodium or potassium),alkaline earth metals (magnesium or calcium), ammonium, organic bases oramino acids, and salts with inorganic acids (hydrochloric acid, sulfuricacid, nitric acid, hydrobromic acid, phosphoric acid and hydroiodicacid), or organic acids (acetic acid, trifluoroacetic acid, citric acid,lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid,mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid,benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, orethanesulfonic acid). Particularly, hydrochloric acid, phosphoric acid,tartaric acid, or methanesulfonic acid is preferable. These salts can beformed by a conventional method.

In addition, the compound (I) is not limited to a specific isomer, butincludes all possible isomers and racemates. For example, when R³ of thecompound (I) is hydroxy, the compound (I) includes other tautomer, thatis, the following compound (I′).

The present compound (I) can be produced by the following process.

(A Process)

wherein R^(A) is an ester residue, R^(B) is hydrogen or hydroxyprotecting group, and other symbols are as defined above.

Herein, the ester residue includes lower alkyl such as methyl, ethyl andthe like, aryl lower alkyl such as benzyl, phenethyl and the like,acyloxy lower alkyl such as acetyloxymethyl and the like, etc.

The hydroxy protecting group is not limited to, but includes lower alkyl(methyl, tert-butyl etc.), aryl lower alkyl (triphenylmethyl, benzyletc.), tri lower alkylsilyl (trimethylsilyl, tert-butyldimethylsilyl,triethylsilyl, triisopropylsilyl etc.), lower alkyldiarylsilyl(tert-butyldiphenylsilyl etc.), triaryl lower alkylsilyl (tribenzylsilyletc.), lower alkoxy lower alkyl (methoxymethyl, 1-ethoxyethyl,1-methyl-1-methoxyethyl etc.), lower alkoxy lower alkoxy lower alkyl(methoxyethoxymethyl etc.), lower alkylthio lower alkyl(methylthiomethyl etc.), optionally substituted tetrahydropyranyl(tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl etc.),tetrahydrothiopyranyl (tetrahydrothiopyran-2-yl etc.), tetrahydrofuranyl(tetrahydrofuran-2-yl etc.), tetrahydrothiofuranyl(tetrahydrothiofuran-2-yl etc.), aryl lower alkyloxy lower alkyl(benzyloxymethyl etc.), lower alkylsulfonyl (methanesulfonyl,ethanesulfonyl etc.), acyl (acetyl etc.) and arylsulfonyl(p-toluenesulfonyl etc.).

(First Step)

First, the known compound or compound (IV) derived therefrom isdeprotected by a conventional method.

For example, when a protecting group is benzyl, the compound isdissolved or suspended in a suitable solvent (ethyl acetate, methanol,ethanol, tetrahydrofuran, dioxane, dimethylformamide, acetic acid,dilute hydrochloric acid, or a mixture thereof), and a hydrogenationreaction using a palladium catalyst (palladium hydroxide,palladium-carbon, palladium-barium sulfate, palladium-aluminum oxide,palladium black etc.) affords compound (III). A reaction may beperformed at about 0° C. to about 100° C., preferably about 20° C. toabout 50° C. for about 15 minutes to about 24 hours, preferably about 1hour to about 5 hours.

(Second Step)

Then, the resulting compound (III) is directly amidated to obtaincompound (Ia).

For example, compound (III) and compound (II) may be reacted by heatingin a suitable solvent (methanol, ethanol, tetrahydrofuran,dimethylformamide, diethyl ether, dichloromethane, dichloroethane,toluene, xylene, chlorobenzene, orthodichlorobenzene, 2-methoxyethanolor diethylene glycol dimethyl ether or a mixture thereof) or without asolvent at about 0° C. to about 250° C., preferably about 80° C. toabout 200° C. for about 30 minutes to about 24 hours, preferably about 1to 12 hours in the presence or the absence of an amine compound(ammonia, dimethylamine, triethylamine, pyridine, dimethylaniline,dimethylaminopyridine, lutidine etc.).

In order to effectively carry a reaction forward, the reaction may beperformed by microwave irradiation. A reaction temperature, and anirradiation time are not particularly limited, but are about 100° C. toabout 200° C. and about 5 minutes to about 5 hours, preferably about 10minutes to about 1 hour. It is preferable to use, as a solvent, a polarsolvent such as methanol, ethanol, 1-propanol, ethylene glycol,glycerin, 2-methoxyethanol, 2-ethoxyethanol, N,N-dimethylformamide,diethylene glycol dimethyl ether and the like.

When R⁴ of objective compound (I) is lower alkyl, an objective compoundcan be obtained by the conventional etherization reaction at anarbitrary stage.

(B Process)

wherein R^(3a) is hydroxy, or optionally substituted lower alkoxy, andother symbols are as defined above.

(First Step)

When R³ of objective compound (I) is optionally substituted loweralkoxy, first, the known compound (IV) is etherized by a conventionalmethod.

For example, the compound is reacted with an alkylating agent or analcohol having a R^(3a) group corresponding to an objective compound inthe presence of a base (sodium hydride, potassium hydride, sodiumhydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide,sodium carbonate, potassium carbonate, calcium carbonate, cesiumcarbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide,sodium bicarbonate or metal sodium), or under the condition of Mitsunobureaction in a suitable solvent (N,N-dimethylformamide, dimethylsulfoxide, toluene, benzene, xylene, a mixture thereof, or the like)cyclohexane, hexane, dichloromethane, 1,2-dichloroethane,tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, acetonitrile,water or a mixture thereof) to obtain compound (VII). The reaction maybe performed at −70 to 180° C., preferably about 0 to 150° C. for about15 minutes to about 24 hours, preferably about 1 hour to about 5 hours.

(Second Step)

Then, compound (VII) is hydrolyzed to obtain compound (VI). The reactionmay be performed under ice-cooling to at a reflux temperature of asolvent for about 15 minutes to about 24 hours, preferably, 1 hour toabout 5 hours using an inorganic base (sodium hydroxide, lithiumhydroxide or potassium hydroxide) in a suitable solvent (methanol,ethanol, tetrahydrofuran, dioxane, dimethylformamide or a mixturethereof).

(Third Step and Fourth Step)

Then, compound (VI) is amidated, and the resulting compound (V) isdeprotected to obtain objective compound (Ib). These reactions may beperformed by the same methods as those of the second step and the firststep in A process, respectively. In an amidation step, the reaction maybe performed, if necessary, in the presence of a condensing agent(N,N′-dicyclohexylcarbodiimide,N-dimethylaminopropyl-N′-ethylcarbodiimide, diethyl phosphoryl cyanide,diphenyl phosphoryl azide etc.).

In addition, when R⁴ of objective compound (I) is lower alkyl, anetherization reaction may be performed at an arbitrary stage asdescribed above.

(C Process)

wherein L is a leaving group, R^(3b) is hydrogen, optionally substitutedlower alkyl, optionally substituted lower alkenyl, optionallysubstituted lower alkynyl, optionally substituted lower alkoxy,mercapto, optionally substituted lower alkylthio, optionally substitutedamino, optionally substituted carbamoyl, optionally substituted aryl, oroptionally substituted heterocyclic group, and other symbols are asdefined above.

(First Step)

When R³ of objective compound (I) is the R^(3b), a leaving group L (e.g.trifluoromethanesulfonyl, methanesulfonyl, phosphoric acid ester etc.)is introduced into the known compound (IV). For example, the compound isreacted with trifluoromethanesulfonic anhydride,trifluoromethanesulfonyl chloride, methanesulfonyl chloride,methanesulfonic anhydride, p-toluenesulfonyl chloride,N-phenyltrifluoromethanesulfonimide or various phosphoric acidesterifying reagents in the presence of a base (pyridine, triethylamine,ammonia, dimethylamine, dimethylaniline, dimethylaminopyridine,2,6-lutidine or 2,6-di-tert-butylpyridine) using dichloromethane,chloroform, tetrahydrofuran, benzene, toluene, dimethylformamide, ethylacetate or a mixture thereof as a solvent.

(Second Step)

The thus obtained compound (VIII) is subjected to the known substituentintroducing reaction to obtain compound (IX).

(Third Step, Fourth Step and Fifth Step)

The compound (IX) is hydrolyzed, amidated, and deprotected by the samemethods as those of the second step in B process, the second step in Aprocess and the first step in A step, respectively, to obtain objectivethe compound (Ic).

In addition, when R⁴ of the objective compound (I) is lower alkyl, anetherization reaction may be performed at an arbitrary stage asdescribed above.

(D Process)

compound (VIII) is obtained by the first step in C process, amidatedaccording to the method of the fourth step in C process, and subjectedto introduction of a substituent R^(3b), deprotection, and a hydrolysisreaction according to the methods of the second step, third step andfifth step in C process, respectively, thereby, objective compound (I)may be also obtained.

All of thus obtained present compounds have the opioid receptorantagonistic activity, and are useful as a drug, and among compoundsrepresented by the formula (I), the following compounds are particularlypreferable.

a) a compound in which R¹ is hydrogen or lower alkyl,b) a compound in which R¹ is hydrogen or C1-C3 alkyl,c) a compound in which R² is:(c-i) lower alkyl optionally substituted with one or more groupsselected from Substituent group β (herein, Substituent group β iscycloalkyl optionally substituted with hydroxy, halogen, hydroxy, loweralkoxy, halogeno lower alkoxy, lower alkylthio, amino, lower alkylamino,carboxy, lower alkoxycarbonyl, cyano, lower alkylsulfonyl, aryl, aryloxyand lower alkylenedioxy),(c-ii) phenyl optionally substituted with one or more groups selectedfrom group consisting of Substituent group β, lower alkyl and halogenolower alkyl,(c-iii) aryl lower alkyl optionally substituted with one or more groupsselected from Substituent group β,(c-iv) cycloalkyl optionally substituted with one or more groupsselected from Substituent group β,(c-v) heterocyclic group optionally substituted with one or more groupsselected from Substituent group β, or(c-vi) heterocyclic lower alkyl optionally substituted with one or moregroups selected from Substituent group β,d) a compound in which R² is:(d-i) lower alkyl optionally substituted with hydroxy, cycloalkyloptionally substituted with hydroxy, lower alkoxy, lower alkylthio,lower alkylamino or aryloxy,(d-ii) phenyl optionally substituted with halogen, lower alkyl, halogenolower alkyl, lower alkoxy, halogeno lower alkoxy, lower alkylthio,amino, lower alkylamino, cyano, lower alkylsulfonyl or loweralkylenedioxy,(d-iii) aryl lower alkyl optionally substituted with lower alkoxy orlower alkylthio,(d-iv) cycloalkyl optionally substituted with lower alkyl, carboxy orlower alkoxycarbonyl,(d-v) a heterocyclic group optionally substituted with lower alkyl,lower alkoxy or phenyl, or(d-vi) heterocyclic lower alkyl optionally substituted with lower alkylor aryl,e) a compound in which R¹ and R² are taken together with a N atom towhich they bind to form a 5-membered or 6-membered saturatedheterocycle,f) a compound in which R³ is hydroxy or lower alkoxy,g) a compound in which R³ is hydroxy,h) a compound in which R³ is amino optionally substituted with one ormore groups selected from Substituent group α,i) a compound in which R³ is halogen, lower alkyl, or amino substitutedwith arylsulfonyl optionally substituted with lower alkoxy,j) a compound in which R⁴ is hydrogen or methoxy,k) a compound in which R⁵ is cycloalkyl lower alkyl or lower alkenyl,l) a compound in which R⁵ is cyclopropylmethyl or allyl,m) a compound in which R⁵ is cyclopropylmethyl,n) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-i),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ is cycloalkyllower alkyl or lower alkenyl,o) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-i),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,p) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-i),R³ is halogen, lower alkyl, or amino substituted with arylsulfonyloptionally substituted with lower alkoxy, R⁴ is hydrogen, and R⁵ iscycloalkyl lower alkyl or lower alkenyl,q) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-i),R³ is halogen, lower alkyl, or amino substituted with arylsulfonyloptionally substituted with lower alkoxy, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,r) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-ii),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ is cycloalkyllower alkyl or lower alkenyl,s) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-ii),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,t) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-iii),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ is cycloalkyllower alkyl or lower alkenyl,u) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-iii),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,v) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-iv),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ is cycloalkyllower alkyl or lower alkenyl,w) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-iv),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,x) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-v),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ is cycloalkyllower alkyl or lower alkenyl,y) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-v),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,z) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-vi),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ is cycloalkyllower alkyl or lower alkenyl,aa) a compound in which R¹ is hydrogen or lower alkyl, R² is the (d-vi),R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,ab) a compound in which R¹ and R² are taken together with a N atom towhich they bind to form a 5-membered or 6-membered saturatedheterocycle, R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ iscycloalkyl lower alkyl group or lower alkenyl,ac) a compound in which R¹ and R² are taken together with a N atom towhich they bind to form a 5-membered or 6-membered saturatedheterocycle, R³ is hydroxy or lower alkoxy, R⁴ is hydrogen, and R⁵ iscyclopropylmethyl,or a pharmaceutically acceptable salt or a solvate thereof.

In a compound represented by the formula (I), a compound in which R⁴ ishydrogen, R⁵ is cyclopropylmethyl, and a combination of NR¹R² and R³(NR¹R², R³) is the following.

TABLE 1

NR1R2 CR9R10 AA —NHiPr — AB

— AC

— AD

— AE

— AF

— AG —NHCR9R10CONH2 Ra AH —NHCR9R10CONH2 Rb AI —NHCR9R10CONH2 Rc AJ—NHCR9R10CONH2 Rd AK —NHCR9R10CONH2 Re AL —NHCR9R10CONH2 Rf AM—NHCR9R10CONH2 Rg AN —NHCR9R10CONH2 Rh AO —NHCR9R10CONH2 Ri AP—NHCR9R10CONH2 Rj AQ —NHCR9R10CONH2 Rk AR —NHCR9R10CONH2 Rl AS—NHCR9R10CONH2 Rm AT —NHCR9R10CONH2 Rn AU —NHCR9R10CONH2 Ro AV—NHCR9R10CONH2 Rp AW —NHCR9R10CONH2 Rq AX —NHCR9R10CONH2 Rr AY—NHCR9R10CONH2 Rs AZ —NHCR9R10CONH2 Rt BA —NHCR9R10CONMe2 Ra BB—NHCR9R10CONMe2 Rb BC —NHCR9R10CONMe2 Rc BD —NHCR9R10CONMe2 Rd BE—NHCR9R10CONMe2 Re BF —NHCR9R10CONMe2 Rf BG —NHCR9R10CONMe2 Rg BH—NHCR9R10CONMe2 Rh BI —NHCR9R10CONMe2 Ri BJ —NHCR9R10CONMe2 Rj BK—NHCR9R10CONMe2 Rk BL —NHCR9R10CONMe2 Rl BM —NHCR9R10CONMe2 Rm BN—NHCR9R10CONMe2 Rn BO —NHCR9R10CONMe2 Ro BP —NHCR9R10CONMe2 Rp BQ—NHCR9R10CONMe2 Rq BR —NHCR9R10CONMe2 Rr BS —NHCR9R10CONMe2 Rs BT—NHCR9R10CONMe2 Rt BU —NHCR9R10COOH Ra BV —NHCR9R10COOH Rb BW—NHCR9R10COOH Rc BX —NHCR9R10COOH Rd BY —NHCR9R10COOH Re BZ—NHCR9R10COOH Rf CA —NHCR9R10COOH Rg CB —NHCR9R10COOH Rh CC—NHCR9R10COOH Ri CD —NHCR9R10COOH Rj CE —NHCR9R10COOH Rk CF—NHCR9R10COOH Rl CG —NHCR9R10COOH Rm CH —NHCR9R10COOH Rn CI—NHCR9R10COOH Ro CJ —NHCR9R10COOH Rp CK —NHCR9R10COOH Rq CL—NHCR9R10COOH Rr CM —NHCR9R10COOH Rs CN —NHCR9R10COOH Rt CO—NHCR9R10COOMe Ra CP —NHCR9R10COOMe Rb CQ —NHCR9R10COOMe Rc CR—NHCR9R10COOMe Rd

TABLE 2 NR1R2 CR9R10 CS —NHCR9R10COOMe Re CT —NHCR9R10COOMe Rf CU—NHCR9R10COOMe Rg CV —NHCR9R10COOMe Rh CW —NHCR9R10COOMe Ri CX—NHCR9R10COOMe Rj CY —NHCR9R10COOMe Rk CZ —NHCR9R10COOMe Rl DA—NHCR9R10COOMe Rm DB —NHCR9R10COOMe Rn DC —NHCR9R10COOMe Ro DD—NHCR9R10COOMe Rp DE —NHCR9R10COOMe Rq DF —NHCR9R10COOMe Rr DG—NHCR9R10COOMe Rs DH —NHCR9R10COOMe Rt DI —NHCR9R10COOEt Ra DJ—NHCR9R10COOEt Rb DK —NHCR9R10COOEt Rc DL —NHCR9R10COOEt Rd DM—NHCR9R10COOEt Re DN —NHCR9R10COOEt Rf DO —NHCR9R10COOEt Rg DP—NHCR9R10COOEt Rh DQ —NHCR9R10COOEt Ri DR —NHCR9R10COOEt Rj DS—NHCR9R10COOEt Rk DT —NHCR9R10COOEt Rl DU —NHCR9R10COOEt Rm DV—NHCR9R10COOEt Rn DW —NHCR9R10COOEt Ro DX —NHCR9R10COOEt Rp DY—NHCR9R10COOEt Rq DZ —NHCR9R10COOEt Rr EA —NHCR9R10COOEt Rs EB—NHCR9R10COOEt Rt EC —NHCR9R10COOiPr Ra ED —NHCR9R10COOiPr Rb EE—NHCR9R10COOiPr Rc EF —NHCR9R10COOiPr Rd EG —NHCR9R10COOiPr Re EH—NHCR9R10COOiPr Rf EI —NHCR9R10COOiPr Rg EJ —NHCR9R10COOiPr Rh EK—NHCR9R10COOiPr Ri EL —NHCR9R10COOiPr Rj EM —NHCR9R10COOiPr Rk EN—NHCR9R10COOiPr Rl EO —NHCR9R10COOiPr Rm EP —NHCR9R10COOiPr Rn EQ—NHCR9R10COOiPr Ro ER —NHCR9R10COOiPr Rp ES —NHCR9R10COOiPr Rq ET—NHCR9R10COOiPr Rr EU —NHCR9R10COOiPr Rs EV —NHCR9R10COOiPr Rt EW—NHCR9R10CONHMe Ra EX —NHCR9R10CONHMe Rb EY —NHCR9R10CONHMe Rc EZ—NHCR9R10CONHMe Rd FA —NHCR9R10CONHMe Re FB —NHCR9R10CONHMe Rf FC—NHCR9R10CONHMe Rg FD —NHCR9R10CONHMe Rh FE —NHCR9R10CONHMe Ri FF—NHCR9R10CONHMe Rj FG —NHCR9R10CONHMe Rk FH —NHCR9R10CONHMe Rl FI—NHCR9R10CONHMe Rm FJ —NHCR9R10CONHMe Rn FK —NHCR9R10CONHMe Ro FL—NHCR9R10CONHMe Rp FM —NHCR9R10CONHMe Rq FN —NHCR9R10CONHMe Rr FO—NHCR9R10CONHMe Rs FP —NHCR9R10CONHMe Rt FQ —NHCR9R10CONHiPr Ra FR—NHCR9R10CONHiPr Rb FS —NHCR9R10CONHiPr Rc FT —NHCR9R10CONHiPr Rd FU—NHCR9R10CONHiPr Re FV —NHCR9R10CONHiPr Rf FW —NHCR9R10CONHiPr Rg FX—NHCR9R10CONHiPr Rh FY —NHCR9R10CONHiPr Ri FZ —NHCR9R10CONHiPr Rj GA—NHCR9R10CONHiPr Rk GB —NHCR9R10CONHiPr Rl GC —NHCR9R10CONHiPr Rm GD—NHCR9R10CONHiPr Rn GE —NHCR9R10CONHiPr Ro GF —NHCR9R10CONHiPr Rp GG—NHCR9R10CONHiPr Rq GH —NHCR9R10CONHiPr Rr GI —NHCR9R10CONHiPr Rs GJ—NHCR9R10CONHiPr Rt GK —NHCR9R10CONHPh Ra GL —NHCR9R10CONHPh Rb GM—NHCR9R10CONHPh Rc GN —NHCR9R10CONHPh Rd GO —NHCR9R10CONHPh Re GP—NHCR9R10CONHPh Rf GQ —NHCR9R10CONHPh Rg GR —NHCR9R10CONHPh Rh GS—NHCR9R10CONHPh Ri GT —NHCR9R10CONHPh Rj GU —NHCR9R10CONHPh Rk GV—NHCR9R10CONHPh Rl GW —NHCR9R10CONHPh Rm GX —NHCR9R10CONHPh Rn GY—NHCR9R10CONHPh Ro GZ —NHCR9R10CONHPh Rp HA —NHCR9R10CONHPh Rq HB—NHCR9R10CONHPh Rr HC —NHCR9R10CONHPh Rs HD —NHCR9R10CONHPh Rt

TABLE 3 NR1R2 CR9R10 HE —NHCR9R10CONHCN Ra HF —NHCR9R10CONHCN Rb HG—NHCR9R10CONHCN Rc HH —NHCR9R10CONHCN Rd HI —NHCR9R10CONHCN Re HJ—NHCR9R10CONHCN Rf HK —NHCR9R10CONHCN Rg HL —NHCR9R10CONHCN Rh HM—NHCR9R10CONHCN Ri HN —NHCR9R10CONHCN Rj HO —NHCR9R10CONHCN Rk HP—NHCR9R10CONHCN Rl HQ —NHCR9R10CONHCN Rm HR —NHCR9R10CONHCN Rn HS—NHCR9R10CONHCN Ro HT —NHCR9R10CONHCN Rp HU —NHCR9R10CONHCN Rq HV—NHCR9R10CONHCN Rr HW —NHCR9R10CONHCN Rs HX —NHCR9R10CONHCN Rt HY—NHCR9R10CONHSO2Me Ra HZ —NHCR9R10CONHSO2Me Rb IA —NHCR9R10CONHSO2Me RcIB —NHCR9R10CONHSO2Me Rd IC —NHCR9R10CONHSO2Me Re ID —NHCR9R10CONHSO2MeRf IE —NHCR9R10CONHSO2Me Rg IF —NHCR9R10CONHSO2Me Rh IG—NHCR9R10CONHSO2Me Ri IH —NHCR9R10CONHSO2Me Rj II —NHCR9R10CONHSO2Me RkIJ —NHCR9R10CONHSO2Me Rl IK —NHCR9R10CONHSO2Me Rm IL —NHCR9R10CONHSO2MeRn IM —NHCR9R10CONHSO2Me Ro IN —NHCR9R10CONHSO2Me Rp IO—NHCR9R10CONHSO2Me Rq IP —NHCR9R10CONHSO2Me Rr IQ —NHCR9R10CONHSO2Me RsIR —NHCR9R10CONHSO2Me Rt IS —NHCR9R10CH2OMe Ra IT —NHCR9R10CH2OMe Rb IU—NHCR9R10CH2OMe Rc IV —NHCR9R10CH2OMe Rd IW —NHCR9R10CH2OMe Re IX—NHCR9R10CH2OMe Rf IY —NHCR9R10CH2OMe Rg IZ —NHCR9R10CH2OMe Rh JA—NHCR9R10CH2OMe Ri JB —NHCR9R10CH2OMe Rj JC —NHCR9R10CH2OMe Rk JD—NHCR9R10CH2OMe Rl JE —NHCR9R10CH2OMe Rm JF —NHCR9R10CH2OMe Rn JG—NHCR9R10CH2OMe Ro JH —NHCR9R10CH2OMe Rp JI —NHCR9R10CH2OMe Rq JJ—NHCR9R10CH2OMe Rr JK —NHCR9R10CH2OMe Rs JL —NHCR9R10CH2OMe Rt JM

Ra JN

Rb JO

Rc JP

Rd JQ

Re JR

Rf JS

Rg JT

Rh

TABLE 4 NR1R2 CR9R10 JU

Ri JV

Rj JW

Rk JX

Rl JY

Rm JZ

Rn KA

Ro KB

Rp KC

Rq KD

Rr KE

Rs KF

Rt KG

Ra KH

Rb KI

Rc KJ

Rd KK

Re KL

Rf KM

Rg KN

Rh KO

Ri KP

Rj KQ

Rk KR

Rl KS

Rm KT

Rn KU

Ro KV

Rp KW

Rq KX

Rr KY

Rs KZ

Rt

TABLE 5 NR1R2 CR9R10 LA

Ra LB

Rb LC

Rc LD

Rd LE

Re LF

Rf LG

Rg LH

Rh LI

Ri LJ

Rj LK

Rk LL

Rl LM

Rm LN

Rn LO

Ro LP

Rp LQ

Rq LR

Rr LS

Rs LT

Rt LU

Ra LV

Rb LW

Rc LX

Rd LY

Re LZ

Rf MA

Rg MB

Rh MC

Ri MD

Rj ME

Rk MF

Rl

TABLE 6 NR1R2 CR9R10 MG

Rm MH

Rn MI

Ro MJ

Rp MK

Rq ML

Rr MM

Rs MN

RtIn the above Tables, CR⁹CR¹⁰ is represented by the following symbol.

TABLE 7 CR9R10 Ra

Rb

Rc

Rd

Re

Rf

Rg

Rh

Ri

Rj

Rk

Rl

Rm

Rn

Ro

Rp

Rq

Rr

Rs

Rt

TABLE 8 R3 VA H VB Me VC OH VD OMe VE CONH2 VF CONHiPr VG NH2 VH NHAc VINHSO2Me VJ Ph VK

VL

VM

VN

VO

VP

VQ

VR

VS NHSO2Ph VT NHCOPh VU CONHMe VV CONMe2 VW NHMe VX NHiPr VY NHPh VZ

WA

WB

WC

(AA,VA), (AA,VB), (AA,VC), (AA,VD), (AA,VE), (AA,VF), (AA,VG), (AA,VH),(AA,VI), (AA,VJ), (AA,VK), (AA,VL), (AA,VM), (AA,VN), (AA,VO), (AA,VP),(AA,VQ), (AA,VR), (AA,VS), (AA,VT), (AA,VU), (AA,VV), (AA,VW), (AA,VX),(AB,VY), (AA,VZ), (AA,WA), (AA,WB), (AA,WC), (AB,VA), (AB,VB), (AB,VC),(AB,VD), (AB,VE), (AB,VF), (AB,VG), (AB,VH), (AB,VI), (AB,VJ), (AB,VK),(AB,VL), (AB,VM), (AB,VN), (AB,VO), (AB,VP), (AB,VQ), (AB,VR), (AB,VS),(AB,VT), (AB,VU), (AB,VV), (AB,VW), (AB,VX), (AB,VY), (AB,VZ), (AB,WA),(AB,WB), (AB,WC), (AC,VA), (AC,VB), (AC,VC), (AC,VD), (AC,VE), (AC,VF),(AC,VG), (AC,VH), (AC,VI), (AC,VJ), (AC,VK), (AC,VL), (AC,VM), (AC,VN),(AC,VO), (AC,VP), (AC,VQ), (AC,VR), (AC,VS), (AC,VT), (AC,VU), (AC,VV),(AC,VW), (AC,VX), (AC,VY), (AC,VZ), (AC,WA), (AC,WB), (AC,WC), (AD,VA),(AB,VB), (AD,VC), (AD,VD), (AD,VE), (AC,VF), (AD,VG), (AD,VH), (AD,VI),(AD,VJ), (AD,VK), (AD,VL), (AD,VM), (AD,VN), (AD,VO), (AD,VP), (AD,VQ),(AD,VR), (AD,VS), (AD,VT), (AD,VU), (AD,VV), (AD,VW), (AC,VX), (AD,VY),(AD,VZ), (AD,WA), (AD,WB), (AD,WC), (AE,VA), (AE,VB), (AE,VC), (AE,VD),(AE,VE), (AE,VF), (AE,VG), (AE,VH), (AE,VI), (AE,VJ), (AE,VK), (AE,VL),(AE,VM), (AE,VN), (AE,VO), (AE,VP), (AE,VQ), (AE,VR), (AE,VS), (AE,VT),(AE,VU), (AE,VV), (AE,VW), (AE,VX), (AB,VY), (AB,VZ), (AE,WA), (AE,WB),(AA,WC), (AF,VA), (AF,VB), (AF,VC), (AF,VD), (AF,VE), (AF,VF), (AF,VG),(AF,VH), (AF,VI), (AF,VJ), (AF,VK), (AF,VL), (AF,VM), (AF,VN), (AF,VO),(AF,VP), (AF,VQ), (AF,VR), (AF,VS), (AF,VT), (AF,VU), (AF,VV), (AF,VW),(AF,VX), (AF,VY), (AF,VZ), (AF,WA), (AF,WB), (AF,WC), (AG,VA), (AG,VB),(AG,VC), (AG,VD), (AG,VE), (AG,VF), (AG,VG), (AG,VH), (AG,VI), (AB,VJ),(AG,VK), (AG,VL), (AB,VM), (AG,VN), (AG,VO), (AG,VP), (AG,VQ), (AG,VR),(AC,VS), (AG,VT), (AG,VU), (AG,VV), (AG,VW), (AG,VX), (AG,VY), (AG,VZ),(AG,WA), (AG,WB), (AA,WC), (AH,VA), (AH,VB), (AH,VC), (AH,VD), (AH,VE),(AH,VF), (AH,VG), (AH,VH), (AH,VI), (AH,VJ), (AH,VK), (AH,VL), (AH,VM),(AH,VN), (AH,VO), (AH,VP), (AH,VQ), (AH,VR), (AH,VS), (AH,VT), (AH,VU),(AH,VV), (AH,VW), (AH,VX), (AH,VY), (AH,VZ), (AH,WA), (AH,WB), (AH,WC),(AI,VA), (AI,VB), (AI,VC), (AI,VD), (AI,VE), (AI,VF), (AI,VG), (AI,VH),(AI,VI), (AI,VJ), (AI,VK), (AI,VL), (AI,VM), (AI,VN), (AI,VO), (AI,VP),(AI,VQ), (AI,VR), (AI,VS), (AI,VT), (AI,VU), (AI,VV), (AI,VW), (AI,VX),(AI,VY), (AI,VZ), (AI,WA), (AI,WB), (AI,WC), (AJ,VA), (AJ,VB), (AJ,VC),(AJ,VD), (AJ,VE), (AJ,VF), (AJ,VG), (AJ,VH), (AJ,VI), (AJ,VJ), (AJ,VK),(AJ,VL), (AJ,VM), (AJ,VN), (AJ,VO), (AJ,VP), (AJ,VQ), (AJ,VR), (AJ,VS),(AJ,VT), (AJ,VU), (AJ,VV), (AJ,VW), (AJ,VX), (AJ,VY), (AJ,VZ), (AJ,WA),(AJ,WB), (AJ,WC), (AK,VA), (AK,VB), (AK,VC), (AK,VD), (AK,VE), (AK,VF),(AK,VG), (AK,VH), (AK,VI), (AK,VJ), (AK,VK), (AK,VL), (AK,VM), (AK,VN),(AK,VO), (AK,VP), (AK,VQ), (AK,VR), (AK,VS), (AK,VT), (AK,VU), (AK,VV),(AH,VW), (AK,VX), (AK,VY), (AK,VZ), (AK,WA), (AK,WB), (AK,WC), (AL,VA),(AL,VB), (AL,VC), (AL,VD), (AL,VE), (AL,VF), (AL,VG), (AL,VH), (AL,VI),(AL,VJ), (AL,VK), (AL,VL), (AL,VM), (AL,VN), (AL,VO), (AL,VP), (AL,VQ),(AL,VR), (AL,VS), (AL,VT), (AL,VU), (AL,VV), (AL,VW), (AL,VX), (AL,VY),(AL,VZ), (AL,WA), (AL,WB), (AL,WC), (AM,VA), (AM,VB), (AM,VC), (AM,VD),(AM,VE), (AM,VF), (AM,VG), (AM,VH), (AM,VI), (AM,VJ), (AK,VK), (AM,VL),(AM,VM), (AM,VN), (AM,VO), (AM,VP), (AM,VQ), (AM,VR), (AM,VS), (AM,VT),(AM,VU), (AM,VV), (AM,VW), (AM,VX), (AM,VY), (AM,VZ), (AM,WA), (AM,WB),(AM,WC), (AN,VA), (AN,VB), (AN,VC), (AN,VD), (AN,VE), (AN,VF), (AN,VG),(AN,VH), (AN,VI), (AN,VJ), (AN,VK), (AN,VL), (AN,VM), (AN,VN), (AN,VO),(AN,VP), (AN,VQ), (AN,VR), (AN,VS), (AN,VT), (AN,VU), (AN,VV), (AN,VW),(AN,VX), (AN,VY), (AN,VZ), (AN,WA), (AN,WB), (AN,WC), (AO,VA), (AO,VB),(AO,VC), (AO,VD), (AO,VE), (AO,VF), (AO,VG), (AO,VH), (AO,VI), (AO,VJ),(AO,VK), (AO,VL), (AO,VM), (AO,VN), (AO,VO), (AO,VP), (AO,VQ), (AO,VR),(AO,VS), (AO,VT), (AO,VU), (AO,VV), (AO,VW), (AO,VX), (AO,VY), (AO,VZ),(AO,WA), (AO,WB), (AO,WC), (AP,VA), (AP,VB), (AP,VC), (AP,VD), (AP,VE),(AP,VF), (AP,VG), (AP,VH), (AP,VI), (AP,VJ), (AP,VK), (AP,VL), 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(LT,VW), (LT,VX), (LT,VY),(LT,VZ), (LT,WA), (LT,WB), (LT,WC), (LU,VA), (LU,VB), (LU,VC), (LU,VD),(LU,VE), (LU,VF), (LU,VG), (LU,VH), (LU,VI), (LU,VJ), (LU,VK), (LU,VL),(LU,VM), (LU,VN), (LU,VO), (LU,VP), (LU,VQ), (LU,VR), (LU,VS), (LU,VT),(LU,VU), (LU,VV), (LU,VW), (LU,VX), (LU,VY), (LU,VZ), (LU,WA), (LU,WB),(LU,WC), (LV,VA), (LV,VB), (LV,VC), (LV,VD), (LV,VE), (LP,VF), (LV,VG),(LV,VH), (LV,VI), (LV,VJ), (LV,VK), (LP,VL), (LV,VM), (LV,VN), (LV,VO),(LV,VP), (LV,VQ), (LV,VR), (LV,VS), (LV,VT), (LV,VU), (LV,VV), (LV,VW),(LV,VX), (LV,VY), (LV,VZ), (LV,WA), (LV,WB), (LV,WC), (LW,VA), (LW,VB),(LW,VC), (LW,VD), (LW,VE), (LW,VF), (LW,VG), (LW,VH), (LW,VI), (LW,VJ),(LW,VK), (LW,VL), (LW,VM), (LW,VN), (LW,VO), (LW,VP), (LW,VQ), (LW,VR),(LW,VS), (LW,VT), (LW,VU), (LW,VV), (LW,VW), (LW,VX), (LW,VY), (LW,VZ),(LW,WA), (LW,WB), (LW,WC), (LX,VA), (LX,VB), (LX,VC), (LX,VD), (LX,VE),(LX,VF), (LX,VG), (LX,VH), (LX,VI), (LX,VJ), (LX,VK), (LX,VL), (LX,VM),(LX,VN), (LX,VO), (LX,VP), (LX,VQ), (LX,VR), (LX,VS), (LX,VT), (LX,VU),(LX,VV), (LX,VW), (LX,VX), (LX,VY), (LX,VZ), (LX,WA), (LX,WB), (LX,WC),(LY,VA), (LY,VB), (LY,VC), (LY,VD), (LY,VE), (LY,VF), (LY,VG), (LY,VH),(LY,VI), (LY,VJ), (LY,VK), (LY,VL), (LY,VM), (LY,VN), (LY,VO), (LY,VP),(LY,VQ), (LY,VR), (LY,VS), (LY,VT), (LY,VU), (LY,VV), (LY,VW), (LY,VX),(LY,VY), (LY,VZ), (LY, WAX (LY,WB), (LY,WC), (LZ,VA), (LZ,VB), (LZ,VC),(LZ,VD), (LZ,VE), (LZ,VF), (LZ,VG), (LZ,VH), (LZ,VI), (LZ,VJ), (LZ,VK),(LZ,VL), (LZ,VM), (LZ,VN), (LZ,VO), (LZ,VP), (LZ,VQ), (LZ,VR), (LZ,VS),(LZ,VT), (LZ,VU), (LZ,VV), (LZ,VW), (LZ,VX), (LZ,VY), (LZ,VZ), (LZ,WA),(LZ,WB), (LZ,WC),(MA,VA), (MA,VB), (MA,VC), (MA,VD), (MA,VE), (MA,VF), (MA,VG), (MA,VH),(MA,VI), (MA,VJ), (MA,VK), (MA,VL), (MA,VM), (MA,VN), (MA,VO), (MA,VP),(MA,VQ), (MA,VR), (MA,VS), (MA,VT), (MA,VU), (MA,VV), (MA,VW), (MA,VX),(MA,VY), (MA,VZ), (MA,WA), (MA,WB), (MA,WC), (MB,VA), (MB,VB), (MB,VC),(MB,VD), (MB,VE), (MB,VF), (MB,VG), (MB,VH), (MB,VI), (MB,VJ), (MB,VK),(MB,VL), (MB,VM), (MB,VN), (MB,VO), (MB,VP), (MB,VQ), (MB,VR), (MB,VS),(MB,VT), (MB,VU), (MB,VV), (MB,VW), (MB,VX), (MB,VY), (MB,VZ), (MB,WA),(MB,WB), (MB,WC), (MC,VA), (MC,VA), (MC,VB), (MC,VB), (MC,VC), (MC,VD),(MC,VE), (MC,VF), (MC,VG), (MC,VH), (MC,VI), (MC,VJ), (MC,VK), (MC,VL),(MC,VM), (MC,VN), (MC,VO), (MC,VP), (MC,VQ), (MC,VR), (MC,VS), (MC,VT),(MC,VU), (MC,VV), (MC,VW), (MC,VX), (MC,VY), (MC,VZ), (MC,WA), (MC,WB),(MC,WC), (MD,VC), (MD,VD), (MD,VE), (MD,VF), (MD,VG), (MD,VH), (MD,VI),(MD,VJ), (MD,VK), (MD,VL), (MD,VM), (MD,VN), (MD,VO), (MD,VP), (MD,VQ),(MD,VR), (MD,VS), (MD,VT), (MD,VU), (MD,VV), (MD,VW), (MD,VX), (MD,VY),(MD,VZ), (MD,WA), (MD,WB), (MD,WC), (ME,VA), (ME,VB), (ME,VC), (ME,VD),(ME,VE), (ME,VF), (ME,VG), (ME,VH), (ME,VI), (ME,VJ), (ME,VK), (ME,VL),(ME,VM), (ME,VN), (ME,VO), (ME,VP), (ME,VQ), (ME,VR), (ME,VS), (ME,VT),(ME,VU), (ME,VV), (ME,VW), (ME,VX), (ME,VY), (ME,VZ), (ME,WA), (ME,WB),(ME,WC), (MF,VA), (MF,VB), (MF,VC), (MF,VD), (MF,VE), (MF,VF), (MF,VG),(MF,VH), (MF,VI), (MF,VJ), (MF,VK), (MF,VL), (MF,VM), (MF,VN), (MF,VO),(MF,VP), (MF,VQ), (MF,VR), (MF,VS), (MF,VT), (MF,VU), (MF,VV), (MF,VW),(MF,VX), (MF,VY), (MF,VZ), (MF,WA), (MF,WB), (MF,WC), (MG,VA), (MG,VB),(MG,VC), (MG,VD), (MG,VE), (MG,VF), (MG,VG), (MG,VH), (MG,VI), (MG,VJ),(MG,VK), (MG,VL), (MG,VM), (MG,VN), (MG,VO), (MG,VP), (MG,VQ), (MG,VR),(MG,VS), (MG,VT), (MG,VU), (ME,VV), (MG,VW), (MG,VX), (MG,VY), (MG,VZ),(MG,WA), (MG,WB), (MG,WC), (MH,VA), (MH,VB), (MH,VC), (MH,VD), (MH,VE),(MH,VF), (MH,VG), (MH,VH), (MH,VI), (MH,VJ), (MH,VK), (MH,VL), (MH,VM),(MH,VN), (MH,VO), (MH,VP), (MH,VQ), (MH,VR), (MH,VS), (MH,VT), (MH,VU),(MH,VV), (MH,VW), (MH,VX), (MH,VY), (MH,VZ), (MH,WA), (MH,WB), (MH,WC),(MI,VA), (MI,VB), (MI,VC), (MI,VD), (MI,VE), (MI,VF), (MI,VG), (MI,VH),(MI,VI), (MI,VJ), (MI,VK), (MI,VL), (MI,VM), (MI,VN), (MI,VO), (MI,VP),(MI,VQ), (MI,VR), (MI,VS), (MI,VT), (MI,VU), (MI,VV), (MI,VW), (MI,VX),(MI,VY), (MI,VZ), (MJ,WA), (MI,WB), (MI,WC), (MJ,VA), (MJ,VB), (MJ,VC),(MJ,VD), (MJ,VE), (MJ,VF), (MJ,VG), (MJ,VH), (MJ,VI), (MJ,VJ), (MJ,VK),(MJ,VM), (MJ,VN), (MJ,VO), (MJ,VP), (MJ,VQ), (MJ,VR), (MJ,VS), (MJ,VT),(MJ,VU), (MJ,VV), (MJ,VW), (MJ,VX), (MJ,VY), (MJ,VZ), (MJ,WA), (MJ,WB),(MJ,WC), (MK,VA), (MK,VB), (MK,VC), (MK,VD), (MK,VE), (MK,VF), (MK,VG),(MK,VH), (MK,VI), (MK,VJ), (MK,VK), (MK,VL), (MK,VM), (MK,VN), (MK,VO),(MK,VP), (MK,VQ), (MK,VR), (MK,VS), (MK,VT), (MK,VU), (MK,VV), (MK,VW),(MK,VX), (MK,VY), (MK,VZ), (MK,WA), (MK,WB), (MK,WC), (ML,VA), (ML,VB),(ML,VC), (ML,VD), (ML,VE), (ML,VF), (ML,VG), (ML,VH), (ML,VI), (ML,VJ),(ML,VK), (ML,VL), (ML,VM), (ML,VN), (ML,VO), (ML,VP), (ML,VQ), (ML,VR),(ML,VS), (ML,VT), (ML,VU), (ML,VV), (ML,VW), (ML,VX), (ML,VY), (ML,VZ),(ML,WA), (ML,WB), (ML,WC), (MM,VA), (MM,VB), (MM,VC), (MM,VD), (MM,VE),(MM,VF), (MM,VG), (MM,VH), (MM,VI), (MM,VJ), (MM,VK), (MM,VL), (MM,VM),(MM,VN), (MM,VO), (MM,VP), (MM,VQ), (MM,VR), (MM,VS), (MM,VT), (MM,VU),(MM,VV), (MM,VW), (MM,VX), (MM,VY), (MM,VZ), (MM,WA), (MM,WB), (MM,WC),(MN,VA), (MN,VB), (MN,VC), (MN,VD), (MN,VE), (MN,VF), (MN,VG), (MN,VH),(MN,VI), (MN,VJ), (MN,VK), (MN,VL), (MN,VM), (MN,VN), (MN,VO), (MN,VP),(MN,VQ), (MN,VR), (MN,VS), (MN,VT), (MN,VU), (MN,VV), (MN,VW), (MN,VX),(MN,VY), (MN,VZ), (MN,WA), (MN,WB), (MN,WC)

As used herein, the “emesis, vomiting and/or constipation” includesnausea, emesis, vomiting and/or constipation which are induced byingestion of a compound having the opioid receptor (particularly, opioidreceptor) agonistic activity. Specifically, examples of the “compoundhaving the opioid receptor agonistic activity” include morphine,oxycodone, fentanyl, methadone, codeine, dihydrocodeine, hydromorphone,levorphanol, meperidine, propoxyphene, dextropropoxyphen, tramadol, anda pharmaceutically acceptable salt, or a solvate thereof. Particularly,when the compound is morphine, oxycodone, or a pharmaceuticallyacceptable salt, or a solvate thereof, the present compound isparticularly effective.

Influence of the present compound on emesis or vomiting can beconfirmed, for example, by the following test.

At thirty minutes after ingestion of a diet, each test substance isadministered to a ferret. The test compound is dissolved in 5% xylitol,and is administered at 5 mg/kg. At thirty minutes after administrationof the test compound, 0.6 mg/kg of morphine was subcutaneouslyadministered, and the vomiting symptom is observed visually until 30minutes after administration of morphine.

For each of emesis (rhythmic constriction movement at an abdominal part)and vomiting (vomiting conduct of excreting a vomiting substance or asimilar conduct), an appearance time, a latent time (time from morphineadministration to initial appearance of vomiting symptom) and asustaining time (time from initial vomiting to final vomiting) arecolleted.

In addition, influence of the present compound on constipation can beconfirmed, for example, by the following test.

1) Preparation of Test Diet (Dye)

Using a 0.5 w/v % Evans Blue aqueous solution, a 2.5 w/v %carboxymethylcellulose salt solution is prepared, and this is used as atest diet.

2) Animal

For example, a Wistar male rat (6 to 7 week old) may be used. The animalis fasted from about 20 or more hours before test initiation, and wateris given ad lib.

3) Test Compound and Medium

The test compound is dissolved in a solvent (DMAA/Solutol/5%meglumine=15/15/70).

DMAA: N,N-dimethylacetamide

Solutol (registered trademark) HS15

Meglumine: D(−)-N-methylglucamine

Morphine hydrochloride is dissolved in a physiological saline.

The test compound, the solvent and morphine are all administered at aliquid amount of 2 mL/kg.

4) Method

The test compound 0.03, 0.1, 0.3, 1 or 3 mg/kg (test compoundadministration group) or the solvent (solvent administration group) issubcutaneously administered, and amount of 3 mg/kg of morphine issubcutaneously administered to all groups after 75 minutes. As a controlgroup, the solvent is subcutaneously administered, and a physiologicalsaline is administered after 75 minutes.

The test diet 2 mL/rat is orally administered at 30 minutes afteradministration of morphine. At fifteen minutes after the test diet (at120 minutes after administration of the test substance), the rats areisolated from esophagus to an ileocecal part near a stomach cardia part.A distance from pyloric part of the stomach to an ileocecal part (fulllength of small intestine) and a distance until a dye reaching frontpart (dye movement distance) are measured.

5) Data Processing

Transport rate(%)=(dye movement distance(cm))/full length of smallintestine(cm))×100

M.P.E.(%)={(small intestine transport rate(%) of each individual of testcompound administration group−average small intestine transport rate(%)of solvent administration group)/(average small intestine transportrate(%) of control group−average small intestine transport rate(%) ofsolvent administration group)}×100

An ED₅₀ value is calculated by reverse estimation of regression a SASprogram using % MPE and letting a value of a control group to be 100%.

The present compound has the opioid receptor (particularly, opioid 8 andμ receptors) antagonistic activity. Therefore, the present compound iseffective in treating and/or preventing digestive tract passage disorderwhich occurs by a cause such as acute dyspepsia, acute alcoholism, foodpoisoning, cold, stomach ulcer, duodenum ulcer, stomach cancer, ileus,appendicitis, peritonitis, cholelithiasis, hepatitis, liverinflammation, encephalitis, meningitis, increased brain pressure, headtrauma, motion sickness, vomiting of pregnancy, side effect due tochemotherapy, side effect due to radiation therapy, side effect due toanti-cancer agent, pressure-stenosis of digestive tract, and intestinaltract coalescence after operation, treating and/or preventing emesis andvomiting which occurs by a cause such as increase in brain pressure dueto brain tumor-brain bleeding-meningitis-irradiation of brain withradiation, and treating and/or preventing acute constipation derivedfrom a cause such as ileus, duodenum ulcer or appendicitis, relaxingconstipation derived from a cause such as nervous disorder, lownutrient, general prostration, vitamin deficiency, anemia, sensitivityreduction or mechanical stimulation insufficiency, or convulsiveconstipation derived from a cause such as stress, in addition toemesis-vomiting-constipation induced by a compound having the opioidreceptor agonistic activity.

Since the present compound has low brain transition, it exhibits thehigh alleviating effect on a side effect such as emesis, vomiting,constipation and the like induced by an opioid receptor agonisticactivity almost without inhibiting the analgesic activity of a compoundhaving the opioid receptor agonistic activity which is administered tothe patient with a decease accompanying pain (e.g. cancerous pain (paindue to bone transition, nervous pressure, increased intracranialpressure, soft tissue infiltration, pain due to constipation or spasm ofmuscle, pain of internal organ, muscle, fascia, waist or shoulder jointperiphery, chronic pain after operation), AIDS etc.). In addition, thepresent compound has pure antagonistic activity on an opioid receptor,and also has an advantage in safety point that the hERG channelinhibitory activity is low, there is no cardiac toxicity, and so on.Further, the present compound also has an advantageous characteristic indynamics in a body such as high oral absorbability, high stability inhuman plasma, high bioavailability and the like, and is very effectiveas a medicament.

When the present compound is administered against emesis, vomiting, orconstipation induced by a compound having the opioid receptor agonisticactivity, the administration may be any of before, after or at the sametime with administration of the compound having the opioid receptoragonistic activity. An administration interval between these two kindsof drugs is not particularly limited. For example, when the presentcompound is administered after administration of the compound having theopioid receptor agonistic activity, if the administration is immediatelyafter to in about 3 days, preferably immediately after to in about 1 dayfrom administration of the compound having the opioid receptor agonisticactivity, the present compound works more effectively. In addition, whenthe present invention is administered before administration of thecompound having the opioid receptor agonistic activity, if theadministration is immediately before to before about 1 day, preferablyimmediately before to before about 12 hours from administration of thecompound having the opioid receptor agonistic activity, the presentcompound works more effectively.

When the present compound is administered as an agent for treatingand/or preventing emesis, vomiting and/or constipation, it may be usedjointly with other agent for treating and/or preventing emesis, vomitingand/or constipation. For example, it is possible to administer the agentjointly with ondansetrone hydrochloride, adrenal cortical steroid(methylprednisolone, prednisolone, dexamethasone etc.),prochlorperazine, haloperidol, thymiperone, perphenazine,metoclopramide, domperidone, scopolamine, chlorpromazine hydrochloride,droperidol, stimulating laxative (sennoside, picosulfate sodium etc.),osmotic laxative (lactulose etc.), or salt laxative (magnesium oxideetc.).

Alternatively, a combination agent between the present compound and acompound having the opioid receptor agonistic activity, or a combinationagent between the present compound and other agent for treating and/orpreventing emesis, vomiting and/or constipation can be administered.

When the present compound is administered to a human, it can beadministered orally as powders, granules, tablets, capsules, pills,solutions, or the like, or parenterally as injectables, suppositories,transdermal absorbable agents, absorbable agents, or the like. Oralagents are preferable.

In addition, the present compound can be formulated into pharmaceuticalpreparations by adding pharmaceutical additives such as excipients,binders, wetting agents, disintegrating agents, lubricants and the like,which are suitable for formulations and, an effective amount of thepresent compound.

The present compound may be formulated into medical mixtures in which acompound having the opioid receptor agonistic activity and/or otheragent for treating and/or preventing emesis, vomiting and/orconstipation and, if necessary, various pharmaceutical additives.

A dose is different depending on state of a disease, an administrationroute, and an age and a weight of a patient, and is usually 0.1 μg to 1g/day, preferably 0.01 to 200 mg/day when orally administered to anadult, and is usually 0.1 μg to 10 g/day, preferably 0.1 to 2 g/day whenparenterally administered.

Following Examples and Test Examples illustrate the present invention inmore detail, but the present invention is not limited by these Examples.

Example 1 Production of Compound (I-4)

wherein Bn indicates benzyl, Et indicates ethyl, and Pr^(i) indicatesisopropyl.

(First step) 7-Ethoxycarbonylnaltrexone

To a suspension of 3-O-benzyl-7-ethoxycarbonylnaltrexone described inNon-Patent Literature 2 (11.16 g, 22.15 mmol) in ethyl acetate (50 mL)and methanol (50 mL) was added palladium hydroxide (Perlman's catalyst)(1.2 g), and the mixture was vigorously stirred for 2 hours under ahydrogen atmosphere. After filtration of the catalyst, the filtrate wasconcentrated, and the residue was crystallized from ethyl acetate andhexane to obtain 8.96 g (92%) of the title compound as colorlesscrystals.

NMR (300 MHz, CDCl₃)

δ 0.14-0.17 (m, 2H), 0.55-0.58 (m, 2H), 0.86 (m, 1H), 1.23-1.29 (m, 3H),1.67 (d, 1H, J=9.6 Hz), 2.02 (dd, 1H, J=1.2, 16.2 Hz), 2.20-2.79 (m,8H), 3.08 (d, 1H, J=18.6 Hz), 3.24 (br, 1H), 4.12-4.20 (m, 2H), 4.96 (s,1H), 5.17 (br, 1H), 6.59 (d, 1H, J=8.1 Hz), 6.72 (d, 1H, J=8.1 Hz),12.12 (s, 1H).

Elemental analysis (C23H27NO6.0.2H2O)

(Calculated value) C, 66.24; H, 6.62; N, 3.36.

(Found value) C, 66.29; H, 6.50; N, 3.45.

(Second step) 7-Isopropylaminocarbonylnaltrexone

A solution of 7-ethoxycarbonylnaltrexone obtained in the first step (200mg, 0.484 mmol), isopropylamine (0.412 mL, 4.84 mmol) and triethylamine(0.202 mL, 1.45 mmol) in 2-methoxyethanol (1.5 mL) was stirred at 180°C. for 45 minutes under microwave irradiation. After cooled to roomtemperature, 7 mL of 5 mol/L hydrochloric acid was added to the reactionmixture, and stirring was continued at 70° C. for 20 minutes. After thereaction solution was cooled, pH value was adjusted to 8.5 with aqueousammonia, followed by extraction with ethyl acetate. The organic layerwas washed with water, and dried, and the solvent was evaporated. Theresidue was purified by silica gel column chromatography(chloroform:methanol=99:1 to 94:6) to obtain 140 mg of the titlecompound at a yield of 68%.

NMR (300 MHz, d6-DMSO)

δ 0.12-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.83 (m, 1H), 1.02 (d, 3H, J=6.6Hz), 1.08 (d, 3H, J=6.6 Hz), 1.41 (d, 1H, J=11.4 Hz), 1.85 (d, 1H,J=15.6 Hz), 2.04-2.62 (m, 8H), 3.04 (d, 1H, J=18.6 Hz), 3.24 (m, 1H),3.96 (m, 1H), 4.71 (s, 1H), 4.74 (s, 1H), 6.51 (d, 1H, J=8.4 Hz), 6.56(d, 1H, J=8.4 Hz), 7.40 (br d, 1H, J=7.2 Hz), 9.16 (s, 1H), 14.50 (s,1H).

Elemental analysis (C24H30N2O5.0.2H2O)

(Calculated value) C, 67.02; H, 7.12; N, 6.51.

(Found value) C, 67.02; H, 7.20; N, 6.49.

Example 2 Preparation of Compound (I-44)

wherein Bn indicates benzyl, Me indicates methyl, Et indicates ethyl,and Pr^(i) indicates isopropyl.

(First step) 3-O-Benzyl-7-ethoxycarbonyl-6-O-methylnaltrexone

To a solution of 3-O-benzyl-7-ethoxycarbonylnaltrexone described inNon-Patent Literature 2 (504 mg, 1 mmol) in tetrahydrofuran (10 mL) weresuccessively added 1,1′-azodicarbonylpiperidine (379 mg, 1.5 mmol),tri-n-butylphosphine (370 μL, 1.5 mmol) and methanol (41 μl, 1 mmol),and the mixture was stirred at room temperature for 7 hours. Thereaction solution was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to obtain the title compound (421 mg, 81%) as colorless oil.

¹H NMR (CDCl₃, δ ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m,1H), 1.26 (t, J=6.6 Hz, 3H), 1.67 (d, J=11.4 Hz, 1H), 2.15-2.80 (m, 8H),3.00-3.30 (m, 2H), 3.93 (s, 3H), 4.05-4.20 (m, 2H), 4.86 (br s, 1H),5.15 (s, 2H), 5.18 (br s, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.1Hz, 1H), 7.28-7.45 (m, 5H)

(Second step) 3-O-Benzyl-7-isopropylaminocarbonyl-6-O-methylnaltrexone

To a mixed solution of 3-O-benzyl-7-ethoxycarbonyl-6-O-methylnaltrexoneobtained in the first step (145 mg, 0.28 mmol) in methanol (6 mL) anddioxane (2 mL) was added a 50% potassium hydroxide aqueous solution (2mL), and the mixture was stirred at 50° C. for 30 minutes. The reactionsolution was cooled to room temperature, and adjusted to pH=4 with 0.5Man aqueous citric acid solution, followed by extraction with ethylacetate. The organic layer was successively washed with water,brinebrine, dried with anhydrous sodium sulfate, and concentrated underreduced pressure. The resulting crystalline residue,3-O-benzyl-7-carboxy-6-O-methylnaltrexone was used in the next reactionwithout purification. To a solution of the above residue indimethylformamide (3 mL) were successively added1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (40 mg, 0.2mmol), 1-hydroxybenzotriazole (27 mg, 0.2 mmol) and isopropylamine (16μL, 0.182 mmol), and the mixture was stirred at room temperature for 15hours. The reaction solution was poured into water and this wasextracted with ethyl acetate, and the organic layer was washed withwater, dried with anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=9/1) to obtain the title compound(39 mg, 44%) as a colorless foam.

¹H NMR (CDCl₃, δ ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m,1H), 1.13 (d, J=2.1 Hz, 3H), 1.15 (d, J=1.8 Hz, 3H), 1.58 (d, J=11.4 Hz,1H), 2.08-2.80 (m, 8H), 2.99-3.30 (m, 2H), 3.94 (s, 3H), 4.06 (m, 1H),4.83 (br s, 1H), 5.14 (d, J=2.4 Hz, 2H), 5.23 (br s, 1H), 6.56 (d, J=8.4Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 7.28-7.45 (m, 6H)

(Third step) 7-Isopropylaminocarbonyl-6-O-methylnaltrexone

To a solution of3-O-benzyl-7-isopropylaminocarbonyl-6-O-methylnaltrexone obtained in thesecond step (33 mg, 0.073 mmol) in tetrahydrofuran (5 mL) was addedpalladium hydroxide (33 mg), and the mixture was stirred for 1 hourunder a hydrogen atmosphere. The reaction solution was filtered withCelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol=9/1) to obtain the title compound (13 mg, 41%) as acolorless foam.

¹H NMR (CDCl₃, δ ppm): 0.10-0.15 (m, 2H), 0.50-0.70 (m, 2H), 0.85 (m,1H), 1.12 (d, J=0.9 Hz, 3H), 1.14 (d, J=0.9 Hz, 3H), 1.66 (d, J=11.4 Hz,1H), 2.06-2.80 (m, 8H), 3.00-3.30 (m, 2H), 3.92 (s, 3H), 4.05 (M, 1H),4.80 (br s, 1H), 5.26 (br s, 1H), 6.56 (d, J=8.1 Hz, 1H), 6.69 (d, J=8.1Hz, 1H), 7.36 (d, J=7.8 Hz, 1H)

Example 3

wherein Bn indicates benzyl, Me indicates methyl, and Et indicatesethyl.

(First Step)

A solution of compound (1) (28.7 g, 57.0 mmol) in tetrahydrofuran (250mL) was cooled to −10° C. and to the solution were1,1′-azodicarbonylpiperidine (21.6 g, 85.5 mol), tri-n-butylphosphine(21.4 mL, 85.5 mmol) and benzyl alcohol (6.50 mL, 62.7 mmol)successively added, and the mixture was stirred at room temperature for6 hours and 45 minutes. The reaction solution was filtered and thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography(chloroform→chloroform/methanol=50/1) to obtain quantitatively theobjective compound (2) (33.8 g) as a pale yellow oil.

¹H NMR (CDCl₃, δ ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m,1H), 0.94 (t, J=7.2 Hz, 3H), 1.20-3.60 (m, 11H), 4.14 (q, J=7.2 Hz, 2H),5.10-5.35 (m, 5H), 6.58 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H),7.15-7.50 (m, 10H)

(Second Step)

To a mixed solution of compound (2) obtained in the first step (33.8 g,57.0 mmol) in methanol (130 mL) and dioxane (43 mL) was added a4N-potassium hydroxide aqueous solution (43 mL), and the mixture wasstirred at 50° C. for 14 hours and 35 minutes. The reaction solution wascooled to room temperature, and concentrated under reduced pressure, andthe residue was adjusted to pH=3 to 4 with ice-water and 2N-hydrochloricacid, followed by extraction with a mixed solution of ethyl acetate andtetrahydrofuran. The organic layer was successively washed with water,and brine, dried with anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was converted into a powder with ether toobtain the objective compound (3) (24.8 g, 77%) as a colorless powder.

¹H NMR (DMSO-d₆, δ ppm): 0.20-0.40 (m, 2H), 0.50-0.65 (m, 2H), 0.95 (m,1H), 1.30-3.60 (m, 11H), 5.00-5.25 (m, 5H), 5.39 (s, 1H), 6.68 (d, J=8.1Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 7.27-7.52 (m, 10H)

(Third Step)

To a solution of compound (3) obtained in the second step (350 mg, 0.619mmol) in tetrahydrofuran (4 mL) were successively added1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (142 mg,0.743 mmol), 1-hydroxybenzotriazole (100 mg, 0.743 mmoL),dimethylglycine methyl ester hydrochloride (114 mg, 0.743 mmol) andN-methylmorpholine (82 μL, 0.743 mmol), and the mixture was stirred atroom temperature overnight. The reaction solution was poured intoice-water snd a saturated sodium bicarbonate aqueous solution, followedby extracted with ethyl acetate, and the organic layer was washed withbrine, dried with anhydrous sodium sulfate, and concentrated under thereduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=50/1) to obtain the objectivecompound (4) (300 mg, 73%) as a pale yellow foam.

¹H NMR (CDCl₃, δ ppm): 0.08-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.87 (m,1H), 1.13 (s, 3H), 1.22 (s, 3H), 1.55-2.80 (m, 11H), 3.62 (s, 3H), 4.85(br s, 1H), 5.13-5.40 (m, 5H), 6.58 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4Hz, 1H), 7.26-7.48 (m, 10H), 7.94 (s, 1H)

(Fourth Step)

To a solution of compound (4) obtained in the third step (290 mg, 0.436mmol) in methanol (4 mL) was added palladium hydroxide (60 mg), followedby stirring for 3 hours under a hydrogen atmosphere. The reactionsolution was filtered with Celite, and the filtrate was concentratedunder reduced pressure. The residue was crystallized with hexane/ethylacetate to obtain the objective compound (I-49) (181 mg, 86%) ascolorless crystals.

¹H NMR (DMSO-d₆, δ ppm): 0.10-0.20 (m, 2H), 0.40-0.57 (m, 2H), 0.84 (m,1H), 1.33 (s, 3H), 1.37 (s, 3H), 1.40-3.40 (m, 11H), 3.55 (s, 3H), 4.72(s, 1H), 4.77 (br s, 1H), 6.52 (d, J=8.1 Hz, 1H), 6.57 (d, J=8.1 Hz,1H), 7.68 (br s, 1H), 9.18 (br s, 1H), 13.78 (br s, 1H)

According to the same procedure, other compounds (I) can be synthesized.Structural formulas and physical constants are shown below.

In Tables, Me indicates methyl, Et indicates ethyl, Pr^(i) indicatesisopropyl, and Ph indicates phenyl.

In addition, in Tables,

TABLE 9 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) δ) I-1

0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 1.87 (m, 1H), 1.13 (t, J = 7.2 Hz,3H), 1.68 (d, J = 11.4 Hz, 1H), 2.20-2.80 (m, 7H), 3.00-3.35 (m, 5H),4.94 (s, 1H), 5.40 (m, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1Hz, 1H), 14.20 8br s, 1H) I-2

0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.85 (m, 1H), 1.41 (d, J = 11.4Hz, 1H), 1.90-3.40 (m, 14H), 4.71 (s, 1H), 4.73 (br s, 1H), 6.50 (d, J =8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 7.77 (br s, 1H) I-3

(CDCl3) 0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.81-0.98 (m, 4H),1.24-1.74 (m, 6H), 2.21-2.77 (m, 7H), 3.05-3.30 (m, 5H), 4.93 (s, 1H),5.40 (br t, 1H), 6.57 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H),14.21 (s, 1H). I-4

0.12-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.83 (m, 1H), 1.02 (d, 3H, J = 6.6Hz), 1.08 (d, 3H, J = 6.6 Hz), 1.41 (d, 1H, J = 11.4 Hz), 1.85 (d, 1H, J= 15.6 Hz), 2.04-2.62 (m, 8H), 3.04 (d, 1H, J = 18.6 Hz), 3.24 (m, 1H),3.96 (m, 1H), 4.71 (s, 1H), 4.74 (s, 1H), 6.51 (d, 1H, J = 8.4 Hz), 6.56(d, 1H, J = 8.4 Hz), 7.40 (br d, 1H, J = 7.2 Hz), 9.16 (s, 1H), 14.50(s, 1H) I-5

0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.40-1.60 (m, 4H),1.83-3.20 (m, 11H), 4.41 (br s, 1H), 4.72 (s, 1H), 4.74 (s, 1H), 6.51(d, J = 8.7 Hz), 6.56 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H), 9.15 (br s,1H), 14.42 (s, 1H). I-6

0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.42 (d, J = 11.7Hz, 1H), 1.83-2.64 (m, 10H), 2.10 (s, 6H), 3.00-3.18 (m, 3H), 4.72 (s,1H), 4.74 (s, 1H), 6.51 (d, J = 8.7 Hz), 6.56 (d, J = 8.7 Hz, 1H), 7.65(s, 1H), 9.10 (br s, 1H). I-7

0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 1.90 (m, 1H), 1.57 (dd, J = 2.4,12.6 Hz, 2H), 1.85-2.80 (m, 10H), 3.00-3.25 (m, 3H), 3.35-3.60 (m, 3H),4.20 (m, 1H), 4.76 (br s, 1H), 5.85 (br s, 1H), 6.58 (d, J = 8.1 Hz,1H), 6.70 (d, J = 8.1 Hz, 1H)

TABLE 10 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) δ) I-8 

0.10-0.20 (m, 2H), 0.45-0.68 (m, 2H), 1.88 (m, 1H), 1.35 (d, J = 11.4Hz, 1H), 1.65-2.20 (m, 4H), 2.30-3.60 (m, 13H), 4.29 (dd, J = 4.8, 12.6Hz, 1H), 5.08 (s, 1H), 5.23 (br s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.57(d, J = 8.1 Hz, 1H), 9.25 (br s, 1H) I-9 

(CDCl3) 0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.62-2.77(m, 6H), 3.07 (d, J = 18.6 Hz, 1H), 3.23 (d, J = 7.2 Hz, 1H), 4.42 (d, J= 5.4 Hz, 2H), 4.93 (s, 1H), 5.66 (br s, 1H), 6.55 (d, J = 8.7 Hz), 6.72(d, J = 8.7 Hz, 1H), 7.22-7.39 (m, 5H), 14.15 (s, 1H). I-10

0.10-0.24 (m, 2H), 0.45-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 11.1Hz, 1H), 1.70-3.40 (m, 10H), 4.78 (s, 1H), 4.82 (s, 1H), 6.54 (d, J =8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 7.05 (m, 1H), 7.29 (t, J = 7.8Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 9.14 (s, 1H), 9.24 (br s, 1H), 13.90(br s, 1H) I-11

0.10-0.22 (m, 2H), 0.44-0.58 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.75-3.40 (m, 10H), 4.78 (s, 1H), 4.83 (s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.13 ( t, J = 8.7 Hz, 2H),7.48-7.56 (m, 2H), 9.17 (s, 1H), 9.27 (br s, 1H), 13.90 (br s, 1H) I-12

0.10-0.18 (m, 2H), 0.52-0.60 (m, 2H), 0.80-0.98 (m, 2H), 0.98-3.21 (m,26H), 4.41 (br, s, 1H), 4.70 (d, J = 12.3 Hz, 1H), 6.55 (d, J = 8.1 Hz,1H), 6.65 (d, J = 8.1 Hz, 1H) I-13

0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 0.87 (m, 1H), 1.58 (d, J = 111.7Hz, 1H), 2.05-2.50 (m, 6H), 2.55-2.90 (m, 5H), 3.00-3.30 (m, 2H), 4.42(s, 1H), 4.81-4.87 (m, 2H), 5.55 (br s, 1H), 6.60 (d, J = 8.1 Hz, 1H),6.72 (d, J = 8.1 Hz, 1H), 7.20-7.40 (m, 5H) I-14

0.10-0.22 (m, 2H), 0.45-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 2.10-3.40 (m, 10H), 3.78 (s, 3H), 4.96 (s, 1H), 6.36 (br s,1H), 6.59 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.84 (d, J =9.0 Hz, 2H), 6.98 (br s, 1H), 7.29 (d, J = 9.0 Hz, 2H), 14.00 (br s, 1H)

TABLE 11 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) δ) I-15

0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.88 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 2.00-3.35 (m, 10H), 3.78 (s, 3H), 4.34 (d, J = 5.1 Hz, 2H),4.91 (s, 1H), 5.61 (br s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.71 (d, J =8.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 14.13(br s, 1H) I-16

0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.84 (s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.30-7.38 (m, 2H), 7.53-7.60 (m,2H), 9.17 (s, 1H), 9.28 (br s, 1H), 13.80 (br s, 1H) I-17

0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 13H), 4.77 (s, 1H), 4.82 (s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.48(d, J = 8.7 Hz, 2H), 9.17 (s, 1H), 9.27 (br s, 1), 13.90 (br s, 1H) I-18

0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.85-3.40 (m, 10H), 3.80 (s, 3H), 4.81 (br s, 2H), 6.52 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.87 (m, 1H), 6.98-7.10 (m, 2H),7.82 (m, 1H), 9.19 (s, 1H), 9.70 (br s, 1H), 12.90 (br s, 1H) I-19

I-20

0.12-0.14 (d, J = 4.5 Hz, 2H), 0.46-0.52 (t, J = 8.3 Hz, 2H), 0.71-0.85(m, 4H), 0.98-1.06 (dd, J = 6.8, 17.3 Hz, 4H), 1.35-1.45 (m, 4H),1.82-1.92 (m, 2H), 2.44-2.61 (m), 3.04 (d, J = 18.9 Hz, 1H), 3.19-3.24(m, 1H), 3.71-3.82 ( m, 1H), 4.71-4.76 (m, 2H), 6.50-6.57 (dd, J = 8.1,14.4 Hz, 2H), 7.31-7.38 (m, 1H), 9.15 (br s, 1H), 14.52 (br s, 1H) I-21

0.12-0.14 (d, J = 4.2 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.69-0.86 (m,6H), 1.32-1.47 (m, 5H), 1.88 (d, J = 15.3 Hz, 1H), 2.06-2.30 (m, 4H),2.45-2.61 (m), 3.04 (d, J = 18.0 Hz, 1H), 3.19-3.24 (m, 1H), 4.71-4.75(m, 2H), 6.05-6.58 (dd, J = 8.8, 14.4 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H),9.15 (br s, 1H), 14.55 (br s, 1H)

TABLE 12 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) δ) I-22

0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.85 (m, 1H),1.06 (m, 1H), 1.16-1.28 (m, 4H), 1.39-1.43 (d, J = 11.4 Hz, 1H),1.54-1.70 (m, 6H), 1.84-1.89 (d, J = 15.6 Hz, 1H), 2.08-2.60 (m, 6H),3.00-3.07 (d, J = 18.6 Hz, 1H), 3.17-3.24 (m, 1H), 3.60 (br s, 1H),4.71-4.76 (m, 2H), 6.49-6.57 (dd, J = 8.1, 14.7 Hz, 2H), 7.37 (d, J =9.0 Hz, 1H), 9.13 (br s, 1H), 14.47 (br s, 1H) I-23

0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 7.8 Hz, 2H), 0.83-0.92 (m,4H), 1.19-1.70 (m, 9H), 1.83-1.93 (m, 1H), 2.06-2.61 (m, 9H), 3.01-3.07(d, J = 18.3 Hz, 1H), 3.18-3.20 (d, J = 4.2 Hz, 1H), 3.67 (m, 1H),4.71-4.76 (m, 2H), 6.52-6.55 (dd, J = 8.1, 14.4 Hz, 2H), 9.13 (br s,1H), 14.48 (br s, 1H) I-24

0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.0 Hz, 2H), 0.83-0.87 (m,1H), 1.34-1.55 (m, 12H), 1.84-1.89 (d, J = 15.6 Hz, 1H), 2.09-2.60 (m,9H), 3.00-3.07 (d, J = 18.3 Hz, 1H), 3.17-3.19 (d, J = 6.0 Hz, 1H),3.78-3.81 (m, 1H), 4.71-4.76 (m, 2H), 6.49-6.57 (dd, J = 8.1, 14.7 Hz,2H), 7.39 (d, J = 8.1 Hz, 1H), 9.13 (br s, 1H), 14.46 (br s, 1H) I-25

0.13-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 7.8 Hz, 2H), 0.85 (m, 1H),1.39-1.43 (d, J = 11.1 Hz, 1H), 1.56-1.64 (m, 2H), 1.85-2.32 (m, 12H),2.43-2.61 (m), 3.01-3.07 (d, J = 18.3 Hz, 1H), 3.18-3.20 (d, J = 6.0 Hz,1H), 4.16-4.27 (m, 1H), 4.72-4.73 (m, 2H), 6.50-6.57 (dd, J = 8.1, 18.9Hz, 2H), 7.77 (d, J = 7.5 Hz, 1H), 9.12 (br s, 1H), 14.41 (br s, 1H)I-26

0.16-0.19 (m, 2H), 0.48-0.57 (m, 2H), 0.88 (m, 1H), 1.46 (d, J = 11.2Hz, 1H), 1.92 (d, J = 15.6 Hz, 1H), 2.04-2.66 (m, 6H), 3.08 (d, J = 18.8Hz, 1H), 3.17-3.40 (m, 6H), 3.24 (s, 3H), 4.77 (s, 1H), 6.55 (d, J = 8.0Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.76 (br t, 1H), 9.15 (s, 1H), 14.33(s, 1H). I-27

0.16-0.19 (m, 2H), 0.48-0..57 (m, 2H), 0.90 (m, 1H), 1.10 (t, J = 6.8Hz, 3H), 1.46 (d, J = 11.2 Hz, 1H), 1.92 (d, J = 15.6 Hz, 1H), 2.04-2.66(m, 6H), 3.08 (d, J = 18.8 Hz, 1H), 3.17-3.46 (m, 8H), , 4.77 (s, 1H),6.55 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.77 (br, 1H), 9.15(s, 1H), 14.32 (s, 1H). I-28

0.16-0.17 (m, 2H), 0.50-0.63 (m, 2H), 0.89 (m, 1H), 1.46 (d, J = 12.0Hz, 1H), 1.92 (d, J = 15.2 Hz, 1H), 2.06 (s, 3H), 2.06-2.70 (m, 6H),3.08 (d, J = 18.4 Hz, 1H), 3.20-3.32 (m, 6H), 4.77 (s, 1H), 6.55 (d, J =8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.76 (br s, 1H), 9.16 (s, 1H),14.31 (s, 1H).

TABLE 13 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) δ) I-29

0.17-0.18 (m, 2H), 0.51-0.57 (m, 2H), 0.90 (m, 1H), 1.46 (d, J = 11.6Hz, 1H), 1.93 (d, J = 16.0 Hz, 1H), 2.11-2.78 (m, 6H), 3.08 (d, J = 18.4Hz, 1H), 3.21 (d, J = 6.0 Hz, 1H), 3.27-3.32 (m, 5H), 4.77 (s, 1H), 6.56(d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.19-7.32 (m, 5H), 7.86(br s, 1H), 9.16 (s, 1H), 14.38 (s, 1H). I-30

0.16-0.19 (m, 2H), 0.48-0.57 (m, 2H), 0.88 (m, 1H), 1.46, (d, J = 11.2Hz, 1H), 1.94 (d, J = 15.6 Hz, 1H), 2.11-2.71 (m, 6H), 3.08 (d, J = 18.8Hz, 1H), 3.49-3.51 (m, 2H), 3.96-4.4.05 (m, 2H), 4.79 (s, 1H), 6.56 (d,J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.94-6.97 (m, 3H), 7.27-7.34(m, 2H), 7.94 (br, 1H), 9.17 (s, 1H), 14.28 (s, 1H). I-31

0.10-0.28 (m, 2H), 0.44-0.65 (m, 2H), 0.94 (m, 1H), 1.50 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.54-7.80 (m, 4H), 9.16 (s, 1H),9.32 (s, 1H), 13.90 (br s, 1H) I-32

0.10-0.25 (m, 2H), 0.42-0.62 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 4.75 (br s, 1H), 4.84,(s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.41-7.54 (m, 4H), 9.17 (s, 1H),9.28 (s, 1H), 13.85 (br s, 1H) I-33

0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.81 (s, 1H), 5.98 (s, 2H),6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.82-6.95 (m, 2H),7.15 (d, J = 1.8 Hz, 1H), 9.16 (s, 1H), 9.26 (s, 1H), 13.98 (br s, 1H)I-34

0.20-0.40 (m, 2H), 0.45-0.65 (m, 2H), 0.90 (m, 1H), 1.50 (m, 1H),1.70-3.40 (m, 10H), 4.65 (br s, 1H), 4.88 (s, 1H), 6.53 (d, J = 8.1 Hz,1H), 6.59 (d, J = 8.1 Hz, 1H), 7.60-7.80 (m, 4H), 9.17 (s, 1H), 9.30 (s,1H), 14.00 (br s, 1H) I-35

0.10-0.20 (m, 2H), 0.50-0.82 (m, 2H), 0.88 (m, 1H), 1.65 (d, J = 10.8Hz, 1H), 2.00-3.80 (m, 14H), 3.78 (s, 3H), 4.93 (s, 1H), 5.46 (br s,1H), 6.57 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.82 (d, J =8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 14.17 (br s, 1H)

TABLE 14 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-36

0.10-0.25 (m, 2H), 0.43-0.63 (m, 2H), 0.88 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 3.71 (s, 3H), 4.77 (s, 1H), 4.82 (s, 1H),6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.64 (m, 1H),7.00-7.25 (m, 3H), 9.17 (s, 1H), 9.27 (s, 1H), 13.90 (br s, 1H) I-37

0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.85 (m, 1H),1.06 (m, 1H), 1.39-1.62 (m, 18H), 1.84-1.89 (d, J = 15.6 Hz, 1H),2.08-2.34 (m, 5H), 2.43-2.54 (m), 2.58-2.60 (d, J = 6.9 Hz, 1H),3.00-3.07 (d, J = 18.6 Hz, 1H), 3.18-3.20 (d, J = 6 Hz, 1H), 3.87 (br s,1H), 4.71-4.76 (m, 2H), 6.49-6.57 (dd, J = 8.1, 14.7 Hz, 2H), 7.38 (d, J= 7.8 Hz, 1H), 9.13 (br s, 1H), 14.47 (br s, 1H) I-38

0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 13H), 4.78 (s, 1H), 4.82 (s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.39(d, J = 8.4 Hz, 2H), 9.17 (s, 1H), 9.27 (s, 1H), 14.00 (br s, 1H) I-39

0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.87 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 16H), 4.76 (s, 1H), 4.80 (s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 9.0 Hz, 2H), 7.29(d, J = 9.0 Hz, 2H), 9.10 (br s, 2H), 14.20 (br s, 1H) I-40

0.10-0.30 (m, 2H), 0.45-0.65 (m, 2H), 0.90 (m, 1H), 1.48 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.85 (s, 1H), 6.54 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.25-7.35 (m, 2H), 7.64 (d, J =9.0 Hz, 2H), 9.18 (s, 1H), 9.29 (s, 1H), 13.90 (br s,

TABLE 15 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-41

0.20-0.40 (m, 2H), 0.45-0.70 (m, 2H), 0.96 (m, 1H), 1.50 (m, 1H),1.70-3.40 (m, 13H), 4.67 (br s, 1H), 4.88 (s, 1H), 6.53 (d, J = 8.1 Hz,1H), 6.59 (d, J = 8.1 Hz, 1H), 7.76 (s, 4H), 9.18 (s, 1H), 9.31 (s, 1H),14.00 (br s, 1H) I-42

0.18 (br, s, 2H), 0.42-0.63 (m, 3H), 0.80-0.97 (m, 2H), 1.20-3.43 (m,24H), 4.92 (s, 1H), 5.89 (br, s, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.71 (d,J = 7.8 Hz, 1H), 14.13 (br, s, 1H) I-43

0.12-0.19 (m, 2H), 0.41-0.58 (m, 2H), 0.74 (d, J = 3.3 Hz, 6H), 1.43 (m,1H), 1.88-3.41 (m, 16H), 4.56 (br, s, 1H), 4.65-4.80 (m, 2H), 6.50-6.62(m, 2H), 7.51 (br, s, 1H), 9.13 (s, 1H), 14.23 (br, s, 1H) I-44

0.10-0.15 (m, 2H), 0.50-0.70 (m, 2H), 0.85 (m, 1H), 1.12 (d, J = 0.9 Hz,3H), 1.14 (d, J = 0.9 Hz, 3H), 1.66 (d, J = 11.4 Hz, 1H), 2.06-2.80 (m,8H), 3.00-3.30 (m, 2H), 3.92 (s, 3H), 4.05 (m, 1H), 4.80 (br s, 1H),5.26 (br s, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H),7.36 (d, J = 7.8 Hz, 1H) I-45

TABLE 16 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-46

0.15-0.35 (m, 2H), 0.45-0.70 (m, 2H), 0.92 (m, 1H), 1.50 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.54-7.74 (m, 4H), 9.16 (s, 1H),9.27 (s, 1H), 14.00 (br s, 1H) I-47

0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.86 (m, 1H), 1.42 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 3.61 (s, 3H), 3.82 (d, J = 5.7 Hz, 2H),4.77 (s, 2H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 8.21(br t, J = 5.7 Hz, 1H), 9.17 (s, 1H), 13.87 (br s, 1H) I-48

0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.89 (m, 1H), 0.90 (d, J = 4.5 Hz,3H), 0.94 (d, J = 4.5 Hz, 3H), 1.45 (s, 9H), 1.66 (d, J = 10.8 Hz, 1H),2.10-3.40 (m, 11H), 4.43 (dd, J = 4.5, 8.1 Hz, 1H), 4.94 (s, 1H), 6.00(d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H),13.99 (br s, 1H) I-49

0.10-0.30 (m, 2H), 0.45-0.70 (m, 2H), 0.90 (m, 1H), 1.34 (s, 3H), 1.38(s, 3H), 1.50-3.40 (m, 11H), 3.56 (s, 3H), 4.77 (br s, 2H), 6.58 (br s,2H), 7.69 (br s, 1H), 9.20 (br s, 1H), 13.76 (br s, 1H) I-50

0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.88 (m, 1H), 1.44 (d, J = 11.7Hz, 1H), 1.90-3.40 (m, 10H), 3.68 (d, J = 4.5 Hz, 2H), 4.77 (s, 1H),6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 8.00 (br, t, J = 4.5hz, 1H), 9.18 (br s, 1H), 14.00 (br s, 1H)

TABLE 17 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-51

0.30-0.50 (m, 2H), 0.55-0.75 (m, 2H), 0.89 (d, J = 3.3 Hz, 3H), 0.91 (d,J = 3.3 Hz, 3H), 1.04 (m, 1H), 1.65 (d, J = 13.5 Hz, 1H), 2.00-3.92 (m,11H), 4.10 (t, J = 6.6 Hz, 1H), 4.95 (s, 1H), 6.64 (d, J = 8.1 Hz, 1H),6.69 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.8 Hz, 9.43 (s, 1H) 13.66 (br s,1H) I-52

0.10-0.25 (m, 2H), 0.45-0.60 (m, 2H), 0.89 (m, 1H), 1.34 (s, 3H), 1.36(s, 3H), 1.46 (d, J = 9.6 Hz, 1H), 1.90-3.40 (m, 10H), 4.75 (s, 1H),6.54 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 9.21(br s, 1H), 14.11 (br s, 1H) I-53

0.13-0.14 (m, 2H), 0.47-0.49 (m, 2H), 0.88 (m, 1H), 1.30 (m, 1H),1.63-2.10 (m, 6H), 2.30-2.70 (m, 4H), 2.96-3.58 (m, 6H), 4.06-4.23 (m,3H), 5.04 (s, 1H), 5.23 (br, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.58 (d, J =8.0 Hz, 1H), 8.08 (br, 1H), 9.23 (br, 1H) . . I-54

0.13-0.14 (m, 2H), 0.47-0.49 (m, 2H), 0.88 (m, 1H), 1.30 (d, J = 12.0Hz, 1H), 1.63-2.12 (m, 6H), 2.28-2.70 (m, 4H), 2.97-3.53 (m, 6H),4.06-4.23 (m, 3H), 5.06 (s, 1H), 5.22 (br, 1H), 6.54 (d, J = 8.0 Hz,1H), 6.58 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 6.4 Hz, 1H), 8.32 (s, 1H),9.23 (br, 1H), 10.97 (s, 1H).

TABLE 18 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-55

0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 4.42 (s, 2H), 4.77 (s, 1H), 5.12 (s, 1H),6.55 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.4 Hz,2H), 7.46 (d, J = 8.4 Hz, 2H), 9.20 (s, 1H), 9.28 (s, 1H), 14.00 (br s,1H) I-56

0.10-0.40 (m, 2H), 0.45-0.70 (m, 2H), 0.92 (m, 1H), 1.29 (t, J = 7.2 Hz,3H), 1.49 (d, J = 9.0 Hz, 1H), 1.70-3.40 (m, 10H), 4.26 (q, J = 7.2 Hz,2H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.59 (d, J= 8.1 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 9.0 Hz, 2H), 9.18(s, 1H), 9.29 (s, 1H) I-57

0.25-0.40 (m, 2H), 0.50-0.70 (m, 2H), 1.00 (m, 1H), 1.56 (d, J = 10.8Hz, 1H), 1.70-3.40 (m, 10H), 4.87 (s, 1H), 4.92 (s, 1H), 6.59 (d, J =8.1 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.86(d, J = 8.4 Hz, 2H), 9.33 (br s, 2H) I-58

0.08-0.20 (m, 2H), 0.43-0.57 (m, 2H), 0.88 (m, 1H), 1.22-3.40 (m, 11H),4.76 (s, 1H), 4.84 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1Hz, 1H), 6.62-6.81 (m, 3H), 7.06-7.16 (m, 2H), 7.73 (s, 1H), 9.16 (s,1H), 9.61 (s, 1H), 13.80 (br s, 1H) I-59

0.08-0.10 (m, 2H), 0.38-0.58 (m, 2H), 0.86 (m, 1H), 1.22-3.40 (m, 17H),4.71 (s, 2H), 6.51 (d, J = 8.1 Hz, 2H), 6.56 (d, J = 8.1 Hz, 1H), 8.58(s, 1H), 9.15 (s, 1H), 14.30 (br s, 1H)

TABLE 19 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-60

0.10-0.20 (m, 2H), 0.45-0.55 (m, 2H), 0.88 (m, 1H), 1.81 (t, J = 7.2 Hz,3H), 1.20-3.75 (m, 20H), 4.07 (q, J = 7.2 Hz, 2H), 5.13 (s, 1H), 5.21(br s, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 9.21b(br s, 1H) I-61

0.11-0.39 (m, 2H), 0.53-0.70 (m, 2H), 0.95 (m, 1H), 1.10-1.20 (m, 3H),1.66-1.73 (m, 1H), 1.82-3.99 (m, 24H), 4.90 (s, 1H), 6.32 (br, s, 1H),6.56 (d, J = 8.4 Hz, 1H), 6.68-6.73 (m, 1H), 14.03 (br, s, 1H) I-62

0.10-0.18 (m, 2H), 0.42-0.56 (m, 2H), 0.85 (m, 1H), 1.03 (d, J = 6.9 Hz,3H), 1.41 (m, 1H), 1.88 (d, J = 15.6 Hz, 1H), 2.04-2.31 (m, 4H), 2.422.62 (m, 6H), 3.04 (d, J = 18.0 Hz, 1H), 3.17-3.35 (m, 7H), 3.87 (m,1H), 4.64 (t, J = 5.7 Hz, 1H), 4.72 (s, 1H), 6.50-6.57 (m, 2H), 7.27 (d,J = 8.1 Hz, 1H), 9.13 (s, 1H), 14.45 (s, 1H) I-63

0.13 (d, J = 4.2 Hz, 2H), 0.43-0.55 (m, 2H), 0.85 (m, 1H), 0.98 (d, J =6.9 Hz, 3H), 1.41 (d, J = 10.8 Hz, 1H), 1.89 (d, J = 15.9 Hz, 1H),2.04-2.32 (m, 4H), 2.43-2.63 (m, 3H), 3.04 (d, J = 18.3 Hz, 1H),3.19-3.40 (m, 11H), 3.86 (m, 1H), 4.72 (s, 1H), 6.50-6.58 (m, 2H), 7.24(m, 1H), 9.14 (s, 1H), 14.41 (br, s, 1H)

TABLE 20 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-64

0.13 (d, J = 4.8 Hz, 2H), 0.43-0.55 (m, 2H), 0.85 (m, 1H), 1.41 (d, J =12.3 Hz, 1H), 1.92 (d, J = 16.2 Hz, 1H), 2.06-2.32 (m, 4H), 2.43-2.61(m, 3H), 3.04 (d, J = 18.3 Hz, 1H), 3.20 (d, J = 6.6 Hz, 1H), 3.33-3.44(m, 4H), 3.82 (m, 1H), 4.59 (t, J = 5.7 Hz, 1H), 4.68 (t, J = 5.7 Hz,1H), 4.73 (s, 2H), 6.50-6.59 (m, 2H), 7.14 (br, s, 1H), 9.14 (s, 1H),14.33 (br, s, 1H) I-65

0.17-0.18 (m, 2H), 0.51-0.53 (m, 2H), 0.92 (m, 1H), 1.34 (m, 1H), 1.35(br s, 9H), 1.71-3.49 (m, 14H), 3.95-4.20 (m, 3H), 5.10 (br, 1H), 5.26(br, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 7.10 (br,1H), 8.35 (s, 1H), 9.24 (s, 1H). I-66

0.41 (m, 1H), 0.50 (m, 1H), 0.60 (m, 1H), 0.69 (m, 1H), 1.08 (m, 1H),1.56 (m, 1H), 1.76-4.29 (m, 17H), 5.19 (s, 1H), 6.66 (d, J = 8.0 Hz,1H), 6.71 (d, J = 8.0 Hz, 1H), 8.14 (br, 1H), 8.20 (br, 1H), 8.98 (br,1H). I-67

0.41 (m, 1H), 0.50 (m, 1H), 0.59 (m, 1H), 0.69 (m, 1H), 1.09 (m, 1H),1.30-4.29 (m, 18H), 5.19 (s, 1H), 5.75 (br, 1H), 6.66 (d, J = 8.4 Hz,1H), 6.71 (d, J = 8.4 Hz, 1H), 8.21 (br, 1H), 8.26 (br, 1H), 8.99 (br,1H).

TABLE 21 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-68

0.17-0.18 (m, 2H), 0.51-0.53 (m, 2H), 0.92 (m, 1H), 1.34 (m, 1H), 1.43(br s, 9H), 1.71-2.03 (m, 5H), 2.18-2.74 (m, 4H), 2.92-3.69 (m, 5H),3.95-4.20 (m, 2H), 5.07 (s, 1H), 5.26 (br, 1H), 6.57 (d, J = 8.0 Hz,1H), 6.61 (d, J = 8.0 Hz, 1H), 7.20 (br, 1H), 9.25 (s, 1H). I-69

0.10-0.26 (m, 2H), 0.42-0.60 (m, 2H), 0.90 (m, 1H), 1.47 (d, J = 10.5Hz, 1H), 1.90-3.40 (m, 10H), 3.84 (s, 3H), 4.81 (br s, 1H), 6.52 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.80 (br s, 1H), 8.08 (br s, 1H),9.18 (br s, 1H), 11.60 (br s, 1H) I-70

0.10-0.20 (m, 2H), 0.40-0.55 (m, 2H), 0.88 (m, 1H), 1.30-4.35 (m, 20H),5.13 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 9.20(br s, 1H) I-71

0.25-0.45 (m, 2H), 0.45-0.70 (m, 2H), 0.97 (m, 1H), 1.64 (d, J = 11.1Hz, 1H), 2.00-3.40 (m, 10H), 4.07 (br s, 1H), 4.97 (s, 1H), 6.63 (d, J =8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 5.4 Hz, 1H), 7.80(d, J = 5.4 Hz, 1H), 9.44 (br s, 1H), 13.40 (br s, 1H) I-72

0.14 (d, J = 4.5 Hz, 2H), 0.40-0.58 (m, 2H), 0.79-0.92 (m, 13H), 1.25(br, s, 1H), 1.41 (m, 1H), 1.907 (s, 1H), 2.11-2.64 (m, 8H), 3.03 (m,1H), 3.21-3.77 (m, 4H), 4.53 (br, s, 1H), 4.72-4.80 (m, 2H), 6.50-6.58(m, 2H), 6.95-7.22 (m, 2H), 9.13 (s, 1H), 14.39 (br, s, 1H)

TABLE 22 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-73

0.14 (d, J = 4.5 Hz, 2H), 0.40-0.58 (m, 3H), 0.74-1.01 (m, 10H),1.25-1.61 (m, 4H), 1.88 (m, 1H), 2.06-2.62 (m, 8H), 3.03 (m, 1H), 3.21(d, J = 6.0 Hz, 1H), 3.45 (t, J = 5.4 Hz, 2H), 3.68 (m, 1H), 4.57 (m,1H), 4.72 (s, 1H), 4.76 (br, s, 1H), 6.51-6.58 (m, 2H), 7.14-7.27 (m,2H), 9.15 (s, 1H), 14.44 (s, 1H) I-74

0.16-0.18 (m, 2H), 0.52 (br d, J = 7.6 Hz, 2H), 0.92 (m, 1H), 1.35 (d, J= 11.2 Hz, 1H), 1.72-3.48 (m, 16H), 4.11-4.29 (m, 3H), 4.73-5.25 (m,2H), 6.57 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 9.23 (s, 1H),11.16 (s, 1H). I-75

0.14-0.15 (m, 2H), 0.43-0.57 (m, 2H), 0.87 (m, 1H), 1.44 (d, J = 11.2Hz, 1H), 1.97 (d, J = 15.6 Hz, 1H), 2.08-3.22 (m, 10H), 4.15-4.48 (m,2H), 4.76 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H),7.23-7.29 (m, 2H), 7.75 (m, 1H), 8.48-8.54 (m, 2H). I-76

0.16-0.17 (m, 2H), 0.50-0.56 (m, 2H), 0.89 (m, 1H), 1.43 (br d, 1H),1.97 (d, J = 15.6 Hz, 1H), 2.11-3.21 (m, 10H), 4.30-4.46 (m, 2H), 4.77(s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.29 (s,2H), 7.44 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 8.42 (br, 1H),9.17 (br, 1H), 14.19 (s, 1H).

TABLE 23 Compound. NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-77

0.10-0.25 (m, 2H), 0.44-0.60 (m, 2H), 0.88 (m, 1H), 1.45 (d, J = 11.1Hz, 1H), 1.70-3.40 (m, 13H), 4.78 (s, 1H), 4.81 (s, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.48(d, J = 9.0 Hz, 2H), 9.15 (s, 1H), 9.25 (s, 1H), 9.88 (s, 1H), 14.00 (brs, 1H) I-78

0.10-0.25 (m, 2H), 0.44-0.60 (m, 2H), 0.89 (m, 1H), 1.17 (t, J = 7.2 Hz,3H), 1.45 (d, J = 11.4 Hz, 1H), 1.70-3.40 (m, 10H), 3.60 (s, 2H), 4.06(q, J = 7.2 Hz, 2H), 4.78 (s, 1H), 4.83 (s, 1H), 6.54 (d, J = 8.1 Hz,1H), 6.58 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 7.45 (d, J =8.7 Hz, 2H), 9.16 (s, 1H), 9.26 (s, 1H), 13.95 (br s, 1H) I-79

0.12-0.30 (m, 2H), 0.44-0.62 (m, 2H), 0.90 (m, 1H), 1.48 (d, J = 11.4Hz, 1H), 1.70-3.40 (m, 10H), 3.51 (s, 2H), 4.81 (s, 1H), 6.55 (d, J =8.1 Hz, 1H), 6.60 (d, J = 8.1 Hz, 11-I), 7.17 (d, J = 8.4 Hz, 2H), 7.44(d, J = 8.4 Hz, 2H), 9.20 (s, 1H), 9.40 (br s, 1H), 14.00 (br s, 1H)I-80

0.10-0.17 (m, 2H), 0.46-0.52 (m, 2H), 0.86 (m, 1H), 1.41 (d, J = 13.2Hz, 1H), 1.87 (m, 1H), 2.09-2.64 (m, 8H), 3.00-3.50 (m, 15H), 4.57 (m,1H), 4.73 (br, s, 2H), 6.50-6.57 (m, 2H), 7.73 (br, s, 1H), 9.14 (s,1H), 14.38 (br, s, 1H) I-81

0.30-0.50 (m, 2H), 0.50-0.70 (m, 2H), 1.05 (m, 1H), 1.50-3.40 (m, 11H),4.58 (s, 1H), 5.39 (s, 1H), 6.52 (d, J = 6.0 Hz, 1H), 6.59 (d, J = 6.0Hz, 1H), 6.84 (br s, 1H), 7.26 (m, 1H), 7.38 (m, 1H), 9.15 (m, 1H)

TABLE 24 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-82

1H-NMR (CDCl3 + CD3OD) d: 0.17 (brs, 2 H), 0.59 (brs, 2 H), 0.89 (brs, 1H), 1.71 (d, J = 10.8 Hz, 1 H), 2.17 (d.d, J = 17.1 & 1.8 Hz, 1 H),2.22- 2.57 (m, 4 H), 2.60-2.84 (m, 3 H), 3.06 (d, J = 15.6 Hz, 1 H),3.24 (brs, 1 H), 4.07 (s, 3 H), 5.31 (s, 1 H), 6.56 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1 H), 7.02-7.10 (m, 1 H), 7.26-7.32 (m, 2 H),7.39 (d.d, J = 8.4 & 0.9 Hz, 2 H), 9.61 (s, 1 H). I-83

1H-NMR (CDCl3 + CD3OD) d: 0.15 (brs, 2 H), 0.58 (brs, 2 H), 0.88 (brs, 1H), 1.49 (t, J = 6.9 Hz, 3 H), 1.68 (d, J = 9.9 Hz, 1 H), 2.15 (d.d, J =17.1 & 1.5 Hz, 1 H), 2.28 (brs, 2 H), 2.39 (brs, 2 H), 2.60-2.80 (m, 3H), 3.06 (d, J = 18.3 Hz, 1 H), 3.26 (brs, 1 H), 4.29 (q, J = 6.9 Hz, 1H), 4.48 (q, J = 6.9 Hz, 1 H), 5.27 (s, 1 H), 6.56 (d, J = 7.8 Hz, 1 H),6.66 (d, J = 7.8 Hz, 1 H), 7.03- 7.09 (m, 1 H), 7.26-7.31 (m, 2 H), 7.50(d.d, J = 8.7 & 0.9 Hz, 2 H). I-84

1H-NMR (CDCl3 + CD3OD) d: 0.16 (brs, 2 H), 0.57 (brs, 2 H), 0.86 (brs, 1H), 1.13 (d, J = 6.6 Hz, 3 H), 1.14 (d, J = 6.6 Hz, 3 H), 1.39 (t, J =6.9 Hz, 3 H), 1.66 (d, J = 9.0 Hz, 1 H), 2.08 (d.d, J = 17.1 & 1.5 Hz, 1H), 2.21 (brs, 2 H), 2.38 (brs, 2 H), 2.58-2.77 (m, 3 H), 3.03 (d, J =18.6 Hz, 1 H), 3.21 (brs, 1 H), 4.03 (quint, J = 6.6 Hz, 1 H), 4.20 (q,J = 6.9 Hz, 1 H), 4.40 (q, J = 6.9 Hz, 1 H), 5.19 (s, 1 H), 6.54 (d, J =8.1 Hz, 1 H), 6.65 (d, J = 8.1 Hz, 1 H), 7.50 (d, J = 7.5 Hz, 1 H).

TABLE 25 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) δ) I-85

1H-NMR (CDCl3 + CD3OD) d: 0.14(brs, 2 H), 0.56 (brs, 2 H), 0.86 (brs, 1H), 1.14 (d, J = 6.6 Hz, 3 H), 1.15 (d, J = 6.6 Hz, 3 H), 1.32 (d, J =4.8 Hz, 1 H), 1.34 (d, J = 4.8 Hz, 3 H), 1.64 (d, J = 9.9 Hz, 1 H), 2.10(d.d, J = 17.1 & 1.5 Hz, 1 H), 2.27 (brs, 2 H), 2.39 (brs, 2 H),2.55-2.77 (m, 3 H), 3.04 (d, J = 18.3 Hz, 1 H), 3.22 (brs, 1 H), 4.03(quint, J = 6.6 Hz, 1 H), 4.81 (quint, J = 6.0 Hz, 1 H), 5.10 (s, 1 H),6.54 (d, J = 8.4 Hz, 1 H), 6.67 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 6.9Hz, 1 H). I-86

1H-NMR (CDCl3 + CD3OD) d: 0.16 (brs, 2 H), 0.568 (brs, 2 H), 0.87 (brs,1 H), 1.67 (d, J = 9.9 Hz, 1 H), 2.14 (d.d, J = 18.3 & 1.2 Hz, 1 H),2.27 (brs, 2 H), 2.41 (brs, 2 H), 3.05 (d, J = 18.6 Hz, 1 H), 3.25 (brd,J = 4.5 Hz, 1 H), 3.92 (s, 1 H), 4.46 (d, J = 5.7 Hz, 2 H), 5.23 (s, 1H), 6.54 (d, J = 8.1 Hz, 1 H), 6.64 (d, J = 8.1 Hz, 1 H), 7.20-7.36 (m,5 H), 8.03 (brt, J = 5.7 Hz, 1 H). I-87

1H-NMR (CDCl3 + CD3OD) d: 0.26 (brs, 2 H), 0.63 (brs, 2 H), 0.94 (brs, 1H), 1.72 (brd, J = 9.0 Hz, 1 H), 2.09-2.93 (m, 8 H), 3.15 (d, J = 18.9Hz, 1 H), 4.97 (s, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 6.70 (d, J = 8.1 Hz,1 H), 7.04-7.08 (m, 1 H), 7.69-7.75 (m, 1 H), 8.13 (d, J = 14.0 Hz, 2H), 8.23 (d, J = 3.9 Hz, 1 H).

TABLE 26 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-89

m/z 462 [M + H]⁺ 0.94 min I-90

m/z 511 [M + H]⁺ 0.63 min I-91

m/z 500 [M + H]⁺ 0.44 min I-92

m/z 462 [M + H]⁺ 0.44 min I-93

m/z 487 [M + H]⁺ 0.50 min

TABLE 27 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-94

m/z 540 [M + H]⁺ 1.07 min I-95

m/z 537 [M + H]⁺ 1.12 min I-96

m/z 581 [M + H]⁺ 1.15 min I-97

m/z 512 [M + H]⁺ 0.50 min I-98

m/z 531 [M + H]⁺ 0.50 min

TABLE 28 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-99 

m/z 537 [M + H]⁺ 1.17 min I-100

m/z 581 [M + H]⁺ 1.15 min I-101

m/z 581 [M + H]⁺ 1.03 min I-102

m/z 538 [M + H]⁺ 0.85 min I-103

m/z 540 [M + H]⁺ 1.05 min

TABLE 29 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-104

m/z 581 [M + H]⁺ 1.12 min I-105

m/z 538 [M + H]⁺ 0.90 min I-106

m/z 537 [M + H]⁺ 1.05 min I-107

m/z 581 [M + H]⁺ 1.09 min

TABLE 30 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-108

m/z 581 [M + H]⁺ 1.03 min I-109

m/z 488 [M + H]⁺ 0.50 min I-110

m/z 518 [M + H]⁺ 0.50 min I-111

m/z 518 [M + H]⁺ 0.56 min I-112

m/z 519 [M + H]⁺ 0.50 min

TABLE 31 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-113

m/z 511 [M + H]⁺ 0.50 min I-114

m/z 486 [M + H]⁺ 0.57 min I-115

m/z 462 [M + H]+ 0.44 min I-116

m/z 497 [M + H]+ 0.63 min I-117

m/z 513 [M + H]+ 0.69 min

TABLE 32 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-118

m/z 493 [M + H]+ 1.06 min I-119

m/z 469 [M + H]+ 0.44 min I-120

m/z 538 [M + H]⁺ 0.94 min I-121

m/z 559 [M + H]⁺ 0.69 min I-122

m/z 559 [M + H]+ 0.69 min

TABLE 33 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-123

m/z 555 [M + H]⁺ 0.56 min I-124

m/z 543 [M + H]⁺ 0.63 min I-125

m/z 425 [M + H]⁺ 0.50 min I-126

m/z 525 [M + H]⁺ 0.56 min I-127

(CDCl3 + CD3OD) d: 0.10- 0.21 (m, 2 H), 0.48-0.63 (m, 2 H), 0.78-0.94(m, 1 H), 1.67 (d, J = 9.6 Hz, 1 H), 2.10-2.50 (m, 6 H), 2.57-2.80 (m, 2H), 3.06 (d, J = 18.6 Hz, 1 H), 3.27 (brs, 1 H), 5.10 (d, J = 1.7 Hz, 1H), 6.31-6.40 (m, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.65 (d, J = 8.1 Hz,1 H), 7.02-7.12 (m, 1 H), 7.22-7.34 (m, 2 H), 7.44- 7.56 (m, 2 H).

TABLE 34 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-128

m/z 553 [M + H]⁺ 0.94 min I-129

m/z 559 [M + H]⁺ 0.63 min I-130

m/z 529 [M + H]⁺ 0.75 min I-131

m/z 497 [M + H]⁺ 0.63 min I-132

m/z 529 [M + H]⁺ 0.88 min

TABLE 35 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-133

m/z 511 [M + H]⁺ 0.97 min 0.12-0.16 (m, 2 H), 0.46-0.52 (m, 2 H), 0.86(m, 1 H), 1.42 (d, J = 10.5 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H),2.06-2.65 (m, 15 H), 3.05 (d, J = 18.3 Hz, 1 H), 3.26 (d, J = 5.9 Hz, 1H), 3.55 (s, 3 H), 4.73 (s, 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.58 (d, J= 8.1 Hz, 1 H), 7.76 (brs, 1 H), 9.31 (brs, 1 H), 13.8 (brs, 1 H) I-134

m/z 498 [M + H]⁺ 0.96 min 0.13-0.16 (m, 2 H), 0.48-0.54 (m, 2 H), 0.87(m, 1 H), 1.43 (d, J = 10.5 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H),2.06-2.67 (m, 15 H), 3.06 (d, J = 18.6 Hz, 1 H), 3.27 (d, J = 6.0 Hz, 1H), 4.73 (s, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H),7.72 (brs, 1 H), 9.20 (brs, 1 H), 14.1 (brs, 1 H) I-135

m/z 483 [M + H]⁺ 0.87 min 0.12-0.14 (m, 2 H), 0.46-0.51 (m, 2 H), 0.85(m, 1 H), 1.06- 1.09 (m, 2 H), 1.35-1.36 (m, 2 H), 1.41 (d, J = 11.7 Hz,1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.17-2.61 (m, 7 H), 3.03 (d, J = 18.3Hz, 1 H), 3.17 (d, J = 6.0 Hz, 1 H), 3.56 (s, 3 H), 4.74 (s, 1 H), 4.77(brs, 1 H), 6.51 (d, J = 8.1 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 9.17(brs, 1 H), 14.1 (brs, 1 H) I-136

m/z 469 [M + H]⁺ 0.89 min 0.12-0.16 (m, 2 H), 0.43-0.51 (m, 2 H), 0.85(m, 1 H), 1.06- 1.12 (m, 2 H), 1.35-1.36 (m, 2 H), 1.42 (d, J = 11.7 Hz,1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.06-2.63 (m, 7 H), 3.02 (d, J = 18.3Hz, 1 H), 3.13 (d, J = 5.4 Hz, 1 H), 4.76 (s, 1 H), 4.77 (brs, 1 H),6.52 (d, J = 8.1 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 9.18 (brs, 1 H),14.1 (brs, 1 H)

TABLE 36 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-137

m/z 539 [M + H]⁺ 0.50 min I-138

m/z 466 [M + H]⁺ 0.57 min I-139

m/z 486 [M + H]⁺ 0.44 min I-140

m/z 520 [M + H]⁺ 0.56 min I-141

m/z 510 [M + H]⁺ 0.75 min

TABLE 37 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-142

m/z 521 [M + H]⁺ 0.50 min I-143

m/z 553 [M + H]⁺ 0.88 min I-144

m/z 494 [M + H]⁺ 0.57 min I-145

m/z 469 [M + H]⁺ 0.83 min I-146

m/z 467 [M + H]+ 1.01 min

TABLE 38 Compound NMR No. Chemical structure LC/MS^(*1) (1H-NMR(d6-DMSO) δ) I-147

m/z 467 [M + H]+ 1.00 min I-148

m/z 559 [M + H]+ 1.16 min** I-149

m/z 598 [M + H]+ 1.34 min** I-150

m/z 514 [M + H]⁺ 0.50 min I-151

m/z 538 [M + H]⁺ 0.63 min

TABLE 39 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-152

m/z 494 [M + H]⁺ 0.56 min I-153

m/z 465 [M + H]⁺ 0.90 min I-154

m/z 465 [M + H]⁺ 0.96 min I-155

m/z 544 [M + H]⁺ 1.00 min I-156

m/z 483 [M + H]⁺ 0.35 min

TABLE 40 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-157

m/z 510 [M + H]⁺ 0.96 min 0.11-0.14 (m, 2H), 0.46-0.50 (m, 2H), 0.83 (m,1H), 0.87 (t, J = 7.2 Hz, 1H), 0.99 (d, J = 4.2 Hz, 3H), 1.01 (d, J =4.2 Hz, 3H), 1.08-1.43 (m, 5H), 1.95 (d, J = 17.1 Hz, 1H), 2.11-2.65 (m,7H), 2.96-3.16 (m, 4H), 3.78 (q, J = 7.5 Hz, 1H), 4.78 (brs, 1H), 5.21(s, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 7.41 (t, J= 5.1 Hz, 1H), 7.50 (d, J = 7.8 Hz, 12H), 9.02 (brs, 1H) I-158

m/z 496 [M + H]⁺ 0.93 min 0.11-0.13 (m, 2H), 0.46-0.50 (m, 2H), 0.85 (m,1H), 1.01 (d, J = 4.1 Hz, 3H), 1.02 (d, J = 4.2 Hz, 3H), 1.07 (d, J =4.0 Hz, 3H), 1.09 (d, J = 4.0 Hz, 3H), 1.40 (d, J = 11.1 Hz, 1H), 1.95(d, J = 17.1 Hz, 1H), 2.09-2.63 (m, 7H), 2.98 (d, J = 18.1 Hz, 1H), 3.13(d, J = 5.4 Hz, 1H), 3.82 (q, J = 6.6 Hz, 1H), 3.88 (q, J = 6.9 Hz, 1H),5.24 (brs, 1H), 5.76 (s, 1H), 6.50 (d, J = 7.5 Hz, 1H), 6.55 (d, J = 7.5Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 6.9 Hz, 1H), 9.01 (brs,1H) I-159

m/z 536 [M + H]⁺ 0.95 min 0.11-0.13 (m, 2H), 0.46-0.50 (m, 2H), 0.83 (m,1H), 0.99 (d, J = 3.0 Hz, 3H), 1.01 (d, J = 3.0 Hz, 3H), 1.15-1.38 (m,6H), 1.40 (d, J = 11.1 Hz, 1H), 1.52-1.80 (m, 4H), 1.97 (d, J = 17.1 Hz,1H), 2.09-2.65 (m, 7H), 2.98 (d, J = 18.6 Hz, 1H), 3.13 (d, J = 5.7 Hz,1H), 3.58 (m, 1H), 3.79 (q, J = 6.9 Hz, 1H), 5.23 (s, 1H), 6.50 (d, J =7.8 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.57(d, J = 7.8 Hz, 1H), 9.00 (brs, 1H)

TABLE 41 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-160

m/z 522 [M + H]⁺ 1.04 min 0.12-0.13 (m, 2H), 0.46-0.51 (m, 2H), 0.85 (m,1H), 0.99 (d, J = 3.3 Hz, 3H), 1.01 (d, J = 3.3 Hz, 3H), 1.15-1.49 (m,7H), 1.91 (d, J = 16.5 Hz, 1H), 2.08-2.65 (m, 7H), 2.98 (d, J = 17.5 Hz,1H), 3.12 (d, J = 5.7 Hz, 1H), 3.16-3.34 (m, 4H), 3.79 (q, J = 6.9 Hz,1H), 4.76 (brs, 1H), 5.01 (s, 1H), 6.54 (d, J = 7.8 Hz, 1H), 6.58 (d, J= 7.8 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 9.01 (brs, 1H) I-161

m/z 524 [M + H]⁺ 0.92 min 0.12-0.14 (m, 2H), 0.46-0.51 (m, 2H), 0.86 (m,1H), 0.99 (d, J = 3.3 Hz, 3H), 1.01 (d, J = 3.3 Hz, 3H), 1.41 (d, J =11.1 Hz, 1H), 1.95 (d, J = 17.1 Hz, 1H), 2.08-2.67 (m, 11H), 2.98 (d, J= 17.5 Hz, 1H), 3.12 (d, J = 5.7 Hz, 1H), 3.49-3.60 (m, 4H), 3.82 (q, J= 6.9 Hz, 1H), 4.78 (brs, 1H), 5.01 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H),6.58 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 9.13 (brs, 1H) I-162

m/z 530 [M + H]⁺ 0.94 min 0.13-0.14 (m, 2H), 0.47-0.51 (m, 2H), 0.83 (m,1H), 0.84 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.44 (d, J =10.5 Hz, 1H), 2.02 (d, J = 16.8 Hz, 1H), 2.11-2.65 (m, 7H), 3.03 (d, J =18.6 Hz, 1H), 3.17 (d, J = 5.7 Hz, 1H), 3.58 (m, 1H), 3.74 (q, J = 6.3Hz, 1H), 4.86 (brs, 1H), 5.39 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.57(d, J = 8.1 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.8 Hz, 2H),7.56 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 9.01 (brs, 1H), 9.70(brs, 1H)

TABLE 42 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-163

m/z 445 [M + H]⁺ 0.83 min I-164

0.14-0.22 (m, 2H), 0.48-0.61 (m, 2H), 0.91 (m, 1H), 1.12 (d, J = 6.6 Hz,6H), 1.53-1.66 (m, 1H), 2.15-2.22 (m, 2H), 2.23- 2.30 (m, 2H), 2.35-2.49(m, 2H), 2.70 (d.d, J = 18.9 & 6.6 Hz, 2H), 3.13 (d, J = 18.9 Hz, 1H),3.27 (d, J = 6.6 Hz, 1H), 3.98 (quintet, J = 6.6 Hz, 1H), 4.99-5.04 (m,1H), 6.32-6.36 (m, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz,1H). I-165

m/z 543 [M + H]⁺ 0.63 min I-166

m/z 446 [M + H]⁺ 0.94 min

TABLE 43 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-167

(CD3OD) d: 0.12-0.22 (m, 2H), 0.48-0.63 (m, 2H), 0.82- 1.00 (m, 1H),1.63 (d, J = 8.1 Hz, 1H), 2.10-2.50 (m, 7H), 2.72 (d.d, J = 18.6 & 6.6Hz, 2H), 3.15 (d, J = 18.6 Hz, 1H), 5.10 (brs, 1H), 6.50-6.65 (m, 3H),7.67 (d.d, J = 4.8 & 1.5 Hz, 1H), 8.36 (d.d, J = 4.8 & 1.5 Hz, 1H).I-168

m/z 582 [M + H]⁺ 0.90 min I-169

m/z 541 [M + H]⁺ 1.15 min I-170

m/z 480 [M + H]⁺ 0.37 min I-171

m/z 509 [M + H]⁺ 0.75 min

TABLE 44 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-172

m/z 505 [M + H]⁺ 0.97 min 0.11-0.13 (m, 2H), 0.46-0.50 (m, 2H), 0.84 (m,1H), 0.98 (d, J = 3.1 Hz, 3H), 1.01 (d, J = 3.1 Hz, 3H), 1.37 (d, J =10.8 Hz, 1H), 2.08 (d, J = 17.4 Hz, 1H), 2.11-2.24 (m, 2H), 2.35 (d, J =6.6 Hz, 1H), 2.51-2.63 (m, 2H), 3.01 (d, J = 18.3 Hz, 1H), 3.13 (d, J =5.7 Hz, 1H), 3.54 (s, 3H), 3.86 (q, J = 7.2 Hz, 1H), 4.79 (brs, 1H),4.98 (brs, 1H), 5.76 (s, 1H), 6.54 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 7.8Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 9.16 (brs, 1H) I-173

m/z 426 [M + H]⁺ 0.90 min 0.12-0.14 (m, 2H), 0.46-0.52 (m, 2H), 0.85 (m,1H), 0.97 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H), 1.03 (d, J =10.2 Hz, 1H), 1.86 (d, J = 15.0 Hz, 1H), 2.02 (d, J = 15.0 Hz, 1H),2.10-2.17 (m, 2H), 2.28 (dd, J = 6.9, 6.9 Hz, 1H), 2.43 (dd, J = 6.9,8.4 Hz, 1H), 2.54-2.62 (m, 2H), 3.01 (d, J = 18.3 Hz, 1H), 3.17 (d, J =5.7 Hz, 1H), 3.58 (m, 1H), 3.88 (q, J = 7.2 Hz, 1H), 4.62 (brs, 1H),4.68 (s, 1H), 6.47 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.94(brs, 1H), 9.06 (brs, 1H) I-174

(CD3OD) d: 0.10-0.25 (m, 2H), 0.48-0.63 (m, 2H), 0.83- 1.00 (m, 1H),1.55 (d, J = 8.1 Hz, 1H), 2.01 (d, J = 15.6 Hz, 1H), 2.22-2.57 (m, 6H),2.70 (d.d, J = 18.3 & 7.2 Hz, 2H), 3.12 (d, J = 18.3 Hz, 1H), 4.67 (s,1H), 6.44-6.62 (m, 3H), 7.54 (d.d, J = 9.6 & 3.6 Hz, 1H), 8.00 (d, J =3.6 Hz, 1H).

TABLE 45 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-175

m/z 458 [M + H]⁺ 0.86 min I-176

ESI: m/z 458 [M + H]⁺ I-177

m/z 460 [M + H]⁺ 1.20 min 0.13-0.17 (m, 2H), 0.47-0.50 (m, 2H), 0.87 (m,1H), 1.41 (d, J = 10.5 Hz, 1H), 2.07 (d, J = 15.0 Hz, 1H), 2.10-2.25 (m,2H), 2.32 (dd, J = 5.7, 6.9 Hz, 1H), 2.45 (dd, J = 5.7, 6.0 Hz, 1H),2.63 (dt, J = 6.3, 11.7, 2H), 3.05 (d, J = 18.3 Hz, 1H), 3.19 (d, J =6.0 Hz, 1H), 4.67 (brs, 1H), 4.75 (s, 1H), 6.51 (d, J = 8.1 Hz, 1H),6.57 (d, J = 8.1 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 8.4 Hz,1H), 7.25 (d, J = 3.6 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 8.38 (brs, 1H),9.07 (brs, 1H)

TABLE 46 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-178

m/z 636 [M + H]⁺ 1.11 min 0.11-0.13 (m, 2H), 0.46-0.51 (m, 2H), 0.86 (m,1H), 0.95 (d, J = 6.6 Hz, 6H), 1.46 (d, J = 11.1 Hz, 1H), 1.87 (d, J =18.0 Hz, 1H), 2.11-2.63 (m, 7H), 2.25 (s, 3H), 3.03 (d, J = 17.4 Hz,1H), 3.18 (brs, 1H), 3.84 (q, J = 7.2 Hz, 1H), 4.71 (brs, 1H), 5.45(brs, 1H), 6.50 (brs, 1H), 6.57 (brs, 1H), 7.61-8.19 (m, 4H), 9.03 (brs,1H), 10.7 (brs, 1H), 12.7 (brs, 1H) I-179

m/z 581 [M + H]⁺ 1.06 min 0.11-0.13 (m, 2H), 0.46-0.51 (m, 2H), 0.86 (m,1H), 0.95 (d, J = 6.6 Hz, 6H), 1.46 (d, J = 11.1 Hz, 1H), 1.87 (d, J =18.0 Hz, 1H), 2.09 (s, 3H), 2.11- 2.63 (m, 7H), 3.03 (d, J = 17.4 Hz,1H), 3.18 (brs, 1H), 3.84 (q, J = 7.2 Hz, 1H), 4.69 (brs, 1H), 5.45(brs, 1H), 6.48 (d, J = 7.2 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 7.33(brd, J = 5.4 Hz, 2H), 7.54 (brs, 1H), 7.74 (d, J = 7.5 Hz, 2H), 9.11(brs, 1H), 12.3 (brs, 1H)

TABLE 47 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-180

m/z 597 [M + H]⁺ 1.03 min 0.11-0.13 (m, 2H), 0.46-0.51 (m, 2H), 0.85 (m,1H), 0.95 (d, J = 6.6 Hz, 6H), 1.46 (d, J = 9.9 Hz, 1H), 1.87 (d, J =17.4 Hz, 1H), 2.11-2.62 (m, 7H), 3.01 (d, J = 17.7 Hz, 1H), 3.15 (d, J =4.6 Hz, 1H), 3.82 (s, 3H), 3.83 (q, J = 5.4 Hz, 1H), 4.67 (brs, 1H),5.44 (s, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 7.04(d, J = 8.4 Hz, 2H), 7.52 (brd, J = 9.3 Hz, 1H), 7.79 (d, J = 8.4 Hz,2H), 9.12 (brs, 1H), 12.2 (brs, 1H) I-181

m/z 502 [M + H]⁺ 0.35 min I-182

m/z 553 [M + H]⁺ 0.68 min I-183

m/z 539 [M + H]⁺ FAB-MS

TABLE 48 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-184

m/z 458 [M + H] + 0.97 min I-185

m/z 519 [M + H]⁺ 0.43 min I-186

m/z 519 [M + H] + 1.67 min** I-187

m/z 539 [M + H]⁺ 0.50 min

TABLE 49 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-188

m/z 505 [M + H]⁺ 0.35 min I-189

m/z 505 [M + H]⁺ 0.42 min I-190

m/z 597 [M + H]⁺ 0.77 min I-191

m/z 523 [M + H]⁺ 1.20 min I-192

m/z 546 [M + H]⁺ 1.00 min

TABLE 50 Compound NMR No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-193

m/z 580 [M + H]⁺ 1.09 min I-194

m/z 474 [M + H] + 0.88 min I-195

m/z 458 [M + H] + 1.08 min I-196

0.12-0.16 (m, 2H), 0.46-0.55 (m, 2H), 0.88 (m, 1H), 1.43 (d, J = 12.4Hz, 1H), 1.65-2.65 (m, 12H), 2.97-3.70 (m, 6H), 3.59 (s, 3H), 4.74 (s,1H), 6.55 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 7.68 (brs, 1H),9.16 (brs, 1H), 13.6 (brs, 1H)

TABLE 51 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-197

0.20-0.40 (m, 2H), 0.46-0.65 (m, 2H), 0.97 (m, 1H), 1.54 (d, J = 6.8 Hz,1H), 1.80-2.10 (m, 3H), 2.31-3.69 (m, 15H), 4.83 (s 1H), 6.59 (d, J =8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 7.56 (brs, 1H), 9.29 (brs, 1H),13.6 (brs, 1H) I-198

m/z 533 [M + H]⁺ 0.95 min 0.11-0.13 (m, 2H), 0.46-0.52 (m, 2H), 0.86 (m,1H), 1.03 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H), 1.46 (brd, J =8.4 Hz, 1H), 1.94 (d, J = 17.7 Hz, 1H), 2.71-2.60 (m, 7H), 2.81 (s, 6H),3.04 (d, J = 17.1 Hz, 1H), 3.18 (brs, 1H), 3.95 (q, J = 5.4 Hz, 1H),4.77 (brs, 1H), 5.45 (s, 1H), 6.51 (d, J = 7.5 Hz, 1H), 6.57 (d, J = 7.5Hz, 1H), 7.64 (brs, 1H), 9.14 (brs, 1H), 12.2 (brs, 1H) I-199

m/z 497 [M + H]⁺ 0.97 min 0.13-0.15 (m, 2H), 0.48-0.52 (m, 2H), 0.86 (m,1H), 1.41 (d, J = 11.4 Hz, 1H), 1.85 (t, J = 7.8 Hz, 2H), 1.93 (d, J =16.5 Hz, 1H), 2.07-2.62 (m, 11H), 3.05 (d, J = 18.3 Hz, 1H), 3.21 (d, J= 6.0 Hz, 1H), 3.59 (s, 3H), 4.72 (s, 1H), 4.77 (brs, 1H), 6.53 (d, J =8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 8.26 (brs, 1H), 9.15 (brs, 1H),14.1 (brs, 1H) I-200

m/z 553 [M + H]⁺ 0.47 min

TABLE 52 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-201

m/z 601 [M + H]⁺ 1.01 min I-202

m/z 563 [M + H]⁺ 0.58 min I-203

m/z 583 [M + H]⁺ 0.54 min I-204

m/z 539 [M + H]⁺ 0.33 min I-205

m/z 573 [M + H]⁺ 0.62 min

TABLE 53 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-206

m/z 535 [M + H]⁺ 0.41 min I-207

m/z 484 [M + H]⁺ 0.32 min I-208

m/z 507 [M + H]⁺ 1.05 min I-209

m/z 518 [M + H] + 1.14 min** I-210

m/z 495 [M + H] + 1.64 min**

TABLE 54 NMR Compound No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-211

m/z 503 [M + H]+ 1.33 min** I-212

m/z 512 [M + H]+ 1.67 min** I-213

m/z 500 [M + H]+ 1.41 min** I-214

m/z 536 [M + H]+ 1.69 min**

TABLE 55 Compound No. Chemical structure LC/MS*¹ NMR (1H-NMR (d6-DMSO)δ) I-215

m/z 485 [M + H]+ 1.60 min** I-216

m/z 565 [M + H]+ 1.82 min** I-217

m/z 548 [M + H]+ 1.17 min** I-218

m/z 512 [M + H]+ 0.95 min** I-219

m/z 512 [M + H]+ 1.66 min** I-220

m/z 525 [M + H]+ 1.60 min** I-221

m/z 521 [M + H]+ 1.35 min**

TABLE 56 Compound No. Chemical structure LC/MS*¹ NMR (1H-NMR (d6-DMSO)δ) I-222

m/z 509 [M + H]+ 1.57 min** I-223

m/z 479 [M + H]+ 1.50 min** I-224

m/z 555 [M + H]+ 1.76 min** I-225

m/z 519 [M + H]+ 1.67 min** I-226

m/z 505 [M + H]+ 1.53 min** I-227

m/z 505 [M + H]+ 1.64 min** I-228

m/z 503 [M + H]+ 1.38 min**

TABLE 57 Compound No. Chemical structure LC/MS*¹ NMR (1H-NMR (d6-DMSO)δ) I-229

m/z 626 [M + H]+ 1.74 min** I-230

m/z 521 [M + H]+ 1.56 min** I-231

m/z 500 [M + H]+ 1.40 min** I-232

m/z 630 [M + H]+ 1.72 min** I-233

m/z 501 [M + H]+ 1.25 min** I-234

m/z 505 [M + H]+ 1.46 min** I-235

m/z 515 [M + H]+ 1.56 min**

TABLE 58 Compound No. Chemical structure LC/MS*¹ NMR (1H-NMR (d6-DMSO)δ) I-236

m/z 565 [M + H]+ 1.77 min** I-237

m/z 501 [M + H]+ 1.17 min** I-238

m/z 548 [M + H]+ 1.29 min** I-239

m/z 518 [M + H]+ 1.21 min** I-240

m/z 542 [M + H]+ 1.31 min** I-241

m/z 520 [M + H]+ 1.50 min** I-242

TABLE 59 Compound NMR No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-243

m/z 493 [M + H]+ 1.05 min I-244

m/z 601 [M + H]+ 1.02 min 0.11-0.13 (m, 2H), 0.48-0.51 (m, 2H), 0.87 (m,1 H), 0.95 (d, J = 6.6 Hz, 6H), 1.48 (d, J = 11.1 Hz, 1H), 1.88 (d, J =18.0 Hz, 1H), 2.10 (s, 3H), 2.18-2.57 (m, 7H), 3.04 (d, J = 16.8 Hz,1H), 3.19 (brs, 1H), 3.78 (q, J = 6.9 Hz, 1H), 4.68 (brs, 1H), 5.43(brs, 1H), 6.49 (d, J = 6.6 Hz, 1H), 6.51 (d, J = 6.6 Hz, 1H), 7.35-7.37(m, 2H), 7.54 (brs, 1H), 7.85 (d, J = 6.9 Hz, 2H), 9.09 (brs, 1H), 12.4(brs, 1H) I-245

m/z 601 [M + H]+ 0.76 min I-246

m/z 505 [M + H]+ 1.38 min** I-247

m/z 521 [M + H]+ 1.58 min**

TABLE 60 Compound NMR No. Chemical structure LC/MS*¹ (1H-NMR (d6-DMSO)δ) I-248

m/z 493 [M + H]+ 1.69 min** I-249

m/z 479 [M + H]+ 1.55 min** I-250

m/z 519 [M + H]+ 1.74 min** I-251

m/z 512 [M + H]+ 0.38 min I-252

0.10-0.15 (m, 2H), 0.34-0.38 (m, 2H), 0.73 (m, 1H), 1.26 (d, J = 9.6 Hz,1H), 1.93-2.54 (m, 10H), 2.94 (d, J = 18.4 Hz, 1H), 3.10 (d, J = 6.0 Hz,1H), 3.67 (s, 3H), 3.72 (s, 3H), 4.58 (s, 1H), 4.84 (s, 1H), 6.42 (d, J= 8.0 Hz, 2H), 6.48 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 9.3 Hz, 2H), 6.69(d, J = 9.2 Hz, 2H), 7.56 (dd, J = 2.8, 8.8 Hz, 1H), 7.66 (dd, J = 2.8,8.8 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.76(s, 1H), 8.97 (s, 1H), 10.78 (s, 1H).

TABLE 61 Compound No. Chemical structure I-253

I-254

I-255

I-256

I-257

TABLE 62 Compound No. Chemical structure I-258

I-259

I-260

I-261

I-262

TABLE 63 Compound No. Chemical structure I-253

I-254

I-255

TABLE 64 Com- pound No. Chemical structure I-266

m/z 457.91 [M + H]+ 0.97 min I-267

m/z 457.91 [M + H]+ 0.62 min I-268

m/z 457.91 [M + H]+ 0.87 min I-269

m/z 473.91 [M + H]+ 0.69 I-270

m/z 457.91 [M + H]+ 0.97 min

TABLE 65 Compound No. Chemical Structure LC/MS*¹ I-271

m/z 520 [M + H]+ 1.63 min** I-272

m/z 513 [M + H]+ 0.45 min I-273

m/z 513 [M + H]+ 0.38 min I-274

m/z 499 [M + H]+ 0.38 min I-275

m/z 548 [M + H]+ 0.38 min

TABLE 66 Compound No. Chemical Structure LC/MS*¹ I-276

m/z 559 [M + H]+ 0.53 min I-277

m/z 610 [M + H]+ 0.46 min I-278

m/z 545 [M + H]+ 0.38 min I-279

m/z 495 [M + H]+ 0.31 min I-280

m/z 545 [M + H]+ 0.97 min

TABLE 67 Compound No. Chemical Structure LC/MS*¹ I-281

m/z 531 [M + H]+ 0.92 min I-282

m/z 455 [M + H]+ 0.87 min I-283

m/z 469 [M + H]+ 0.94 min I-284

m/z 571 [M + H]+ 0.68 min I-285

m/z 509 [M + H]+ 0.32 min

TABLE 68 Compound No. Chemical Structure LC/MS*¹ I-286

m/z 471 [M + H]+ 0.32 min I-287

m/z 455 [M + H]+ 0.90 min I-288

m/z 501 [M + H]+ 0.32 min I-289

m/z 584 [M + H]+ 0.46 min (LC/MS conditions of measurement)*1: Column:Chromolith Flash ROD RP-18e. 25 × 4.6 mm I.D. Flow Rate: 2 ml/min UVDetector: 280 nm Solvent System: [A] = H2O_0.05% HCOOH [B] = MeOH_0.05%HCOOH Gradient: 0 min; 90% [A]_10% [B] 0.2 min; 90% [A]_10% [B] 1.0 min;10% [A]_90% [B] 1.80 min; 10% [A]_90% [B] Proviso, values with symbol **follow below conditions of measurement Column: Phenomenex Luna 5 μC18(2) 100A, size 50 × 4.60 mm Gradient: 10%-100% Acetonitrile linearduring 3.0 min at 3.0 mL/min

Test Example 1 Binding Assay of Opioid S Receptor 1) Method of PreparingMembrane Specimen for Binding Assay

A rat cerebrum (Slc: SD) which had been stored at −80° C. was used. To acerebrum which had been weighed was added a 20-fold amount of ice-cooled10 mM Tris-HCl buffer (pH 7.0), and the mixture was homogenized (25000rpm, 30 seconds) with Histocolon (NITI-ON), and centrifuged at 36600×gfor 20 minutes. To the resulting pellet was added 15 ml of the samebuffer, and the mixture was treated with Histocolon similarly, andcentrifuged. This washing work was performed two times. Aftercentrifugation, to the resulting pellet was added 15 mL of a 50 mMTris-HCl buffer (pH 7.4), and this was treated with Histocolon, andfinally resuspended in a 10-fold amount of the same buffer, which wasused as a crude membrane fraction (Life Sci. 48, 111-116, 1991). Theprepared membrane specimen was frozen and stored at −80° C., and at anassay, the specimen was rapidly thawed, and diluted to about 900 μg/mLwith a 50 mM Tris-HCl buffer (pH 7.4) after the centrifugation andHistocolon treatment, and was used in an experiment. For measuring aprotein concentration of the membrane specimen, Micro BCA Protein AssayKit (PIERCE) was used.

2) Method of δ Receptor Binding Assay and Data Analysis

To a solution of 10 μl of the test compound diluted at 10-fold stage wasadded 10 μl of final 3 nM [³H]-DADLE (51.5 Ci/mmol: PerkinElmer) as aligand. Into a tube was placed 480 μl of a rat cerebrum membranefraction to which 100 mM choline chloride, 3 mM MnCl₂ and 100 nM DAMGOhad been added, and this was incubated at 25° C. for 2 hours. Afterincubation, this was suction-filtered with a Whatman GF/C filter whichhad been pre-treated with 0.5% polyethyleneimine, and washed with 2.5 mLof an ice-cooled 10 mM Tris-HCl buffer (pH7.4) four times. Afterwashing, the filter was transferred to a mini vial for liquidscintillation counter, 5 mL of a scintillator (Cleasol I) was added,this was allowed to stand overnight, and the radioactivity was measuredfor 3 minutes with a liquid scintillation counter Tri-Carb 2200CA(PACKARD). DMSO was used for total binding (Total bound: TB) for dataanalysis, and 20 μM levallorphan was used for non-specific binding(Non-specific bound: NB), and a Ki value of the test compound wascalculated using a KD value (2.93 nM) obtained in advance by Scatchardplot analysis.

Results are shown in Table 69.

TABLE 69 test compound Ki (nM) I-3 8.76 I-4 7.38 I-7 7.4 I-10 19.92 I-135.02 I-30 5.34 I-39 41.8 I-49 3.99 I-92 5.23 I-118 27.65 I-133 9.85I-135 9.76 I-145 13.87 I-188 3.01 I-199 12.77 I-208 13.28 I-229 5.9I-240 11.5 I-243 5.2 I-244 0.56 I-267 41.46 I-283 3.73 I-284 0.91 I-2855.77 I-286 2.46 I-288 5.36 I-289 0.47

From the above results, it is seen that compound (I) has an affinity foran opioid δ receptor.

Test Example 2 Bindind Assay to Opioid μ Receptor 1) Method of PreparingMembrane Specimen for Binding Assay

A rat cerebrum (Slc: SD) which had been stored at −80° C. was used. To acerebrum which had been weighed was added a 20-fold amount of ice-cooled10 mM Tris-HCl buffer (pH 7.0), the mixture was homogenized (25000 rpm,30 seconds) with Histocolon (NITI-ON), and centrifuged at 36600×g for 20minutes. To the resulting pellet was added 15 ml of the same buffer, andthe mixture was treated with Histocoln similarly, and centrifuged. Thiswashing work was performed two times. After centrifugation, to theresulting pellet was added 15 mL of a 50 mM Tris-HCl buffer (pH 7.4),this was treated with Histocolon, and this was finally resuspended in a10-fold amount of the same buffer, which was used as a crude membranefraction (Life Sci. 48, 111-116, 1991). The prepared membrane specimenwas frozen and stored at −80° C., and at a test, the specimen wasrapidly thawed, and diluted to about 900 μg/mL with a 50 mM Tris-HClbuffer (pH 7.4) after the centrifugation and Histocolon treatment, andwas used in an experiment. For measuring a protein concentration of themembrane specimen, Micro BCA Protein Assay Kit (PIERCE) was used.

2) Method of μ Receptor Binding Assay and Data Analysis

To a solution of 10 μl of the test compound diluted at 10-fold stagediluted test compound was added 10 μl of final 2 nM [³H]-DAMGO (51.5Ci/mmol: PerkinElmer) as a ligand, further, 4800 of a rat cerebrummembrane fraction was placed into a tube, and this was incubated at 25°C. for 2 hours. After incubation, this was suction-filtered with aWhatman GF/C filter which had been pre-treated with 0.5%polyethyleneimine, and washed with 2.5 mL of an ice-cooled 10 mMTris-HCl buffer (pH 7.4) four times. After washing, the filter wastransferred to a mini vial for liquid scintillation counter, 5 mL of ascintillator (Cleasol I) was added, and this was allowed to standovernight, and the radioactivity was measured for 3 minutes with aliquid scintillation counter Tri-Carb 2200CA (PACKARD). DMSO was usedfor total binding (Total bound: TB) for data analysis, and 20 μMlevallorphan was used for non-specific binding (Non-specific bound: NB),and a Ki value of the test compound was calculated using a KD value(1.72 nM) obtained in advance by Scatchard plot analysis (Anal. Biochem.107(1), 220-239, 1980).

Results are shown in Table 70.

TABLE 70 test compound Ki (nM) I-4 5.18 I-10 4.05 I-39 0.33 I-49 16.49I-118 2.29 I-122 2.7 I-123 1.68 I-124 3.9 I-133 4.99 I-135 1.58 I-13815.53 I-145 28.09 I-188 17.27 I-199 9.45 I-208 5.89 I-229 1.3 I-240 6.85I-243 5.28 I-244 11.02 I-267 0.84 I-283 20.14 I-284 1.13 I-285 7.29I-286 13.98 I-288 14.38 I-289 12.95

Test Example 3 Mouse Carbon Powder Transport Assay 1) Preparation ofTest Diet (Carbon Powder)

Using a 10 w/v % arabic gum aqueous solution, a 5 w/v % active carbonsolution was prepared, which was used as a test diet.

2) Animal

A ddY line male mouse (5 to 6 weeks old) was used. The mouse was fastedfrom about 20 or more hours before assay initiation, and water was givenad lib.

3) Test Compound and Medium

The test compound was dissolved in a solvent (DMAA/Solutol/5%meglumine=15/15/70).

DMAA: N,N-dimethylacetamide

Solutol: Solutol (registered trademark) HS15

Meglumine: D(−)-N-methylglucamine

Morphine hydrochloride was dissolved in a physiological saline. The testcompound, the above solvent and morphine were all administered at aliquid amount of 10 mL/kg.

4) Assay Method

The test compound 3 mg/kg (test compound administration group) or thesolvent (solvent administration group) were subcutaneously administeredand, after 15 minutes, amount of 3 mg/kg of morphine was administered toall groups. As a control group, the solvent was subcutaneouslyadministered and, after 15 minutes, a physiological saline wasadministered.

The test diet 10 mL/kg was orally administered at 15 minutes afteradministration of morphine. At thirty minutes after administration ofthe test diet (60 minutes after administration of the test substance),all mice were isolated from esophagus to an ileocecal part near astomach cardia part. A distance from pyloric part of the stomach to anileocecal part (full length of small intestine) and a distance until acarbon powder reaching front part (carbon powder movement distance) weremeasured. The antagonistic activity on the carbon powder transport ofinhibitory activity by morphine was calculated as MPE (%) using thefollowing equation. Results are shown in Table 71.

Transport rate(%)=(carbon powder movement distance)/full length of smallintestine(cm))×100

M.P.E.(%)={(small intestine transport rate(%) of each individual of testcompound administration group−average small intestine transport rate(%)of solvent administration group)/(average small intestine transportrate(%) of control group−average small intestine transport rate(%) ofsolvent administration group)}×100

TABLE 71 test compound M.P.E. (%) I-39 52 I-49 80 I-118 55.6 I-122 31.5I-123 44.1 I-124 46.6 I-133 106.9 I-135 59.7 I-138 55.8 I-145 60.2 I-18874.6 I-199 62.8 I-208 81.2 I-229 39.7 I-240 36.3 I-243 52.6 I-244 71.6I-267 60 I-283 63.7 I-284 79.6 I-285 82.5 I-286 70.6 I-288 101.3 I-28967

Formulation Example 1

A granule containing the following ingredients is prepared.

Ingredient Compound represented by formula (I) 10 mg Lactose 700 mg Cornstarch 274 mg HPC-L 16 mg 1000 mg

The compound represented by the formula (I) and lactose are passedthrough a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve.These are mixed with a V-type mixer. To a mixed powder is added a HPC-L(lower viscosity hydroxypropylcellulose) aqueous solution, the materialsare kneaded, granulated (extrusion granulation, pore diameter 0.5 to 1mm), and dried. The resulting dry granule is passed through a sieveusing a vibration sieve (12/60 mesh) to obtain a granule.

Formulation Example 2

A granule for filling into a capsule containing the followingingredients is prepared.

Ingredient Compound represented by formula (I) 15 mg Lactose 90 mg Cornstarch 42 mg HPC-L  3 mg 150 mg 

The compound represented by the formula (I) and lactose are passedthrough a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve.These are mixed, to a mixed powder is added a HPC-L solution, thematerials are kneaded, granulated, and dried. The resulting dry granuleis size-adjusted, 150 mg of which is filled into a No. 4 hard gelatincapsule.

Formulation Example 3

A tablet containing the following ingredients is prepared.

Ingredient Compound represented by the formula (I) 10 mg Lactose 90 mgMicrocrystalline cellulose 30 mg CMC-Na 15 mg Magrnesium stearate  5 mg150 mg 

The compound represented by the formula (I), lactose,microcrystallinecellulose, CMC-NA (carboxymethylcellulose sodium salt)are passed through a 60 mesh sieve, and mixed. Into a mixed powder ismixed magnesium stearate to obtain a mixed powder for tabletting. Thepresent mixed powder is compressed to obtain 150 mg of a tablet.

Formulation Example 4

The following ingredients are warmed, mixed, and sterilized to obtain aninjectable.

Ingredient Compound represented by the formula (I) 3 mg Nonionicsurfactant 15 mg Purified water for injection 1 ml

INDUSTRIAL APPLICABILITY

The present invention is useful as an agent for alleviating a sideeffect such as emesis, vomiting and/or constipation.

1. A compound represented by the formula (I):

wherein R¹ and R² are each independently hydrogen, optionallysubstituted lower alkyl, optionally substituted lower alkenyl,optionally substituted lower alkynyl, optionally substituted loweralkylsulfonyl, optionally substituted acyl, optionally substitutedcycloalkyl, optionally substituted cycloalkenyl, optionally substitutedaryl, an optionally substituted heterocyclic group, optionallysubstituted arylsulfonyl, or R¹ and R² are taken together with thenitrogen atom to which they are atttached to form optionally substitutedheterocycle; R³ is hydrogen, hydroxy, optionally substituted loweralkyl, optionally substituted lower alkenyl, optionally substitutedlower alkynyl, optionally substituted lower alkoxy, mercapto, optionallysubstituted lower alkylthio, optionally substituted amino, optionallysubstituted carbamoyl, optionally substituted acyl, optionallysubstituted acyloxy, optionally substituted aryl, or an optionallysubstituted heterocyclic group; a group represented by the formula:

wherein ring A and ring B are each independently optionally substitutednitrogen-containing heterocycle optionally containing additionalnitrogen atom, oxygen atom, and/or sulfur atom in the ring; broken lineindicates the presence or the absence of a bond; when broken lineindicates the presence of a bond, p is 0; when a broken line indicatesthe absence of a bond, p is 1; R^(a) is hydrogen, optionally substitutedlower alkyl, optionally substituted lower alkenyl, or optionallysubstituted lower alkynyl; and R^(b) is hydrogen or oxo; R⁴ is hydrogenor lower alkyl; R⁵ is hydrogen, lower alkyl, cycloalkyl lower alkyl orlower alkenyl, or a pharmaceutically acceptable salt, or a solvatethereof.
 2. The compound according to claim 1, wherein R³ is hydroxy, ora pharmaceutically acceptable salt, or a solvate thereof.
 3. Thecompound according to claim 1, wherein R³ is optionally substitutedamino, or a pharmaceutically acceptable salt, or a solvate thereof. 4.The compound in any one of claims 1 to 3, wherein R¹ is hydrogen orlower alkyl, R² is optionally substituted lower alkyl, optionallysubstituted phenyl, optionally substituted cycloalkyl, or an optionallysubstituted heterocyclic group, and R⁵ is cyclopropylmethyl, or apharmaceutically acceptable salt, or a solvate thereof.
 5. Apharmaceutical composition containing a compound in any one of claims 1to 4, or a pharmaceutically acceptable salt, or a solvate thereof.
 6. Acomposition having an opioid receptor antagonistic activity containing acompound in any one of claims 1 to 4, or a pharmaceutically acceptablesalt, or a solvate thereof.
 7. A composition for treating and/orpreventing emesis, vomiting and/or constipation containing a compound inany one of claims 1 to 4, or a pharmaceutically acceptable salt, or asolvate thereof.
 8. A composition for alleviating and/or preventing aside effect induced by a compound having opioid receptor agonisticactivity containing a compound in any one of claims 1 to 4, or apharmaceutically acceptable salt, or a solvate thereof.
 9. An agent fortreating and/or preventing a side effect according to claim 8, whereinthe side effect is emesis, vomiting and/or constipation.
 10. Acomposition for treatment and/or prevention according to claim 8 or 9,wherein the compound having the opioid receptor agonistic activity ismorphine, oxycodone, or a pharmaceutically acceptable salt, or a solvatethereof.
 11. Use of the compound in any one of claims 1 to 4, or apharmaceutically acceptable salt, or solvate thereof, for preparation ofa pharmaceutical composition for treating and/or preventing emesis,vomiting and/or constipation.
 12. A method for treating and/orpreventing emesis, vomiting and/or constipation, comprisingadministering the compound in any one of claims 1 to 4, or apharmaceutically acceptable salt, or a solvate thereof.
 13. Acomposition for analgesic containing a compound having an opioidreceptor agonistic activity, and an effective amount of compoundaccording to any one of claims 1 to 4, or a pharmaceutically acceptablesalt, or a solvate thereof, for alleviating and/or preventing a sideeffect induced by administrating of the compound having an opioidreceptor agonistic activity